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Allele Symbol Allele Name Allele ID |
Tg(Mx1-cre)1Cgn transgene insertion 1, University of Cologne MGI:2176073 |
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| Summary |
310 genotypes
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• when Cdkn1ctm2.1Kei is inherited maternally, hematopoietic stem (KSL) cells from pIpC-treated mice exhibit reduced colony formation in vitro before and after coculture with OP9 cells compared with control cells
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• when Cdkn1ctm2.1Kei is inherited maternally, mice exhibit decreased KSL fractions as early as 4 weeks after pIpC-treatment compared with control mice
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• when Cdkn1ctm2.1Kei is inherited maternally, hematopoietic stem cells from pIpC-treated mice exhibit decreased self-renewal capacity, decreased maintenance of quiescence, and increased frequency of apoptosis compared with control mice
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• when bone marrow is transplanted into CD45.1+ wild-type hosts reconstitution is normal
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
 |
• 6 months after induction with poly(I:C) (pIpC), multipotent progenitor cell populations increase in percentage and total number in bone marrow
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• 6 months after induction with poly(I:C) (pIpC), multi-lineage, mixed granulocyte/erythroid/macrophage/megakaryocyte (GEMM) colonies increase in percentage and total number in bone marrow
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• 6 months after induction with poly(I:C) (pIpC), viable long term hematopoietic stem cells and short term hematopoietic stem cells increase in percentage and total number in bone marrow
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• following induction with poly(I:C), mice exhibit reduced clearance of S. aureus compared to wild-type mice
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• after Poly(I) Poly(C) induction of cre expression mice develop the lymphoproliferative disease seen in Fastm1.1Cgn homozygtes
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• PIPC treated-mice die between 6 and 20 months of age with a median survival time of 10 months
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• spleen size in PIPC treated-mice is 2.5-fold greater than normal at 2 months of age and 5-fold greater at 12 months of age
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• bone marrow and spleen cells of PIPC treated-mice produce more colony forming units-granulocyte/monocyte (CFU-GM) than in wild-type cultures
• however, the number of burst-forming units-erythroid is normal
• cultured bone marrow and spleen cells of PIPC treated-mice produce more immature cells than wild-type cultures
• transplanted bone marrow cells of PIPC treated-mice are capable of producing bone marrow hypercellularity and splenomegaly in recipients
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• in PIPC treated-mice
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• B cell maturation in PIPC treated-mice is blocked resulting in decreased pre-B cells and increased pro-B cells compared to in wild-type mice
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• in some older PIPC treated-mice
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• bone marrow and spleen cells of PIPC treated-mice produce more colony forming units-granulocyte/monocyte (CFU-GM) in culture compared to wild-type cells
• however, the number of burst-forming units-erythroid is normal
• cultured bone marrow and spleen cells of PIPC treated-mice produce more immature cells than wild-type cultures
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• at 12 months, bone marrow of PIPC treated-mice becomes hypercellular with accumulation of immature myeloid cells and increased mononuclear cell numbers unlike in wild-type mice
• the fraction of undifferentiated or partially differentiated myeloid cells in PIPC treated-mice is increased compared to in wild-type mice
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• at 2 months, megakaryocyte populations in the bone marrow of PIPC treated-mice are reduced compared to in wild-type mice
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• at 2 months, erythrocyte populations in the bone marrow of PIPC treated-mice are reduced compared to in wild-type mice
• at 12 months, PIPC treated-mice mice exhibit a decrease in the number of Ter119 cells in the bone marrow
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• at 12 months of age but not 2 months of age in PIPC treated-mice
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• in the bone marrow and spleen in PIPC treated-mice
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• slightly at 2 months of age in PIPC treated-mice
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• slightly at 2 months of age in PIPC treated-mice
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• slightly at 2 months of age in PIPC treated-mice
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• B lymphoid populations in the spleen are reduced compared to in wild-type mice
• at 2 months and 12 months of age, B lymphoid populations in the bone marrow of PIPC treated-mice are reduced compared to in wild-type mice
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• in the bone marrow at 12 months of age in PIPC treated-mice
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• at 12 months of age in PIPC treated-mice
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• granulocyte and monocyte populations of PIPC treated-mice are expanded in the spleen compared to in wild-type mice
• at 2 months, granulocyte populations in the bone marrow of PIPC treated-mice are expanded compared to in wild-type mice
• at 12 months, the bone marrow of PIPC treated-mice contains more Gr-1 cells than in wild-type mice
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• at 12 months of age in PIPC treated-mice
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• granulocyte and monocyte populations from PIPC treated-mice are expanded in the spleen compared to in wild-type mice
• at 2 months, monocyte populations in the bone marrow of PIPC treated-mice are expanded compared to in wild-type mice
• at 12 months, the bone marrow of PIPC treated-mice contains more Mac-1 cells than in wild-type mice
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• the number of Lin-/low and/or c-KIT+ cells in the bone marrow of PIPC treated-mice is increased at 2 months of age, and even more so at 12 months of age, compared to in wild-type mice
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• white pulp in PIPC treated-mice contains more immature myeloid less and fewer mature lymphocytes than in wild-type mice
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• at 2 months, areas of myeloproliferation in PIPC treated-mice are found within the red pulp unlike in wild-type mice
• at 12 months, PIPC treated-mice mice exhibit progressive myeloproliferation with expansion mostly of immature myeloid cells in the red pulp unlike in wild-type mice
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• bone marrow cells of PIPC treated-mice can be cultured for longer than wild-type cells without immortalization and with reduced requirement of cytokines
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• spleen size in PIPC treated-mice is 2.5-fold greater than normal at 2 months of age and 5-fold greater at 12 months of age
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• in PIPC treated-mice
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• B cell maturation in PIPC treated-mice is blocked resulting in decreased pre-B cells and increased pro-B cells compared to in wild-type mice
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• in the bone marrow and spleen in PIPC treated-mice
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• slightly at 2 months of age in PIPC treated-mice
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• slightly at 2 months of age in PIPC treated-mice
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• slightly at 2 months of age in PIPC treated-mice
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• B lymphoid populations in the spleen are reduced compared to in wild-type mice
• at 2 months and 12 months of age, B lymphoid populations in the bone marrow of PIPC treated-mice are reduced compared to in wild-type mice
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• in the bone marrow at 12 months of age in PIPC treated-mice
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• at 12 months of age in PIPC treated-mice
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• granulocyte and monocyte populations of PIPC treated-mice are expanded in the spleen compared to in wild-type mice
• at 2 months, granulocyte populations in the bone marrow of PIPC treated-mice are expanded compared to in wild-type mice
• at 12 months, the bone marrow of PIPC treated-mice contains more Gr-1 cells than in wild-type mice
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• at 12 months of age in PIPC treated-mice
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• granulocyte and monocyte populations from PIPC treated-mice are expanded in the spleen compared to in wild-type mice
• at 2 months, monocyte populations in the bone marrow of PIPC treated-mice are expanded compared to in wild-type mice
• at 12 months, the bone marrow of PIPC treated-mice contains more Mac-1 cells than in wild-type mice
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• white pulp in PIPC treated-mice contains more immature myeloid less and fewer mature lymphocytes than in wild-type mice
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• at 2 months, areas of myeloproliferation in PIPC treated-mice are found within the red pulp unlike in wild-type mice
• at 12 months, PIPC treated-mice mice exhibit progressive myeloproliferation with expansion mostly of immature myeloid cells in the red pulp unlike in wild-type mice
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• spleen size in PIPC treated-mice is 2.5-fold greater than normal at 2 months of age and 5-fold greater at 12 months of age
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• in mice fed a high iron diet and treated with pIpC
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• in mice fed a high iron diet and treated with pIpC
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• in mice fed a high iron diet and treated with pIpC
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• in mice fed a high iron diet and treated with pIpC
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• mice fed a high iron diet and treated with pIpC exhibit liver damage (including increased liver weight, swollen liver, enlarged nuclei, macrosteatosis, hemorrhage, infiltration of polymorphonuclear cells, hepatocyte apoptosis, and decreased liver function) and increased lethality compared with Fth1tm1.1Lck homozygotes fed a high iron diet
• pIpC-treated mice injected with iron-dextran exhibit acute liver damage unlike iron-dextran-treated Fth1tm1.1Lck homozygotes
• however, no liver damage is observed in pIpC treated mice fed standard chow
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• in reticuloendothelial cells of pIpC-treated mice
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• mild in pIpC-treated mice
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• in mice fed a high iron diet and treated with pIpC
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• in mice fed a high iron diet and treated with pIpC
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• mice fed a high iron diet and treated with pIpC exhibit swollen livers with infiltration of polymorphonuclear cells unlike in Fth1tm1.1Lck homozygotes fed a high iron diet
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• macrosteatosis in mice fed a high iron diet and treated with pIpC
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• in reticuloendothelial cells of pIpC-treated mice
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• mice fed a high iron diet and treated with pIpC exhibit swollen livers with infiltration of polymorphonuclear cells unlike in Fth1tm1.1Lck homozygotes fed a high iron diet
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• in mice fed a high iron diet and treated with pIpC
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• in reticuloendothelial cells of pIpC-treated mice
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• bone marrow cells transplanted into lethally irradiated recipients and treated with pIpC and tamoxifen results in death in a 100% of animals in a 440 day period
• in 33% of mice death is the result of myeloproliferative disorder (MPD)
• in 67% of mice death is the result of mixed myelodysplastic syndrome and myeloproliferative disorder (MDS/MPD)
• bone marrow cells from MDS/MPD or MPD primary transplants transplanted into sublethally irradiated secondary recipients results in 100% lethality due to acute myeloid leukemia (AML)
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• Cd11b+Gr+ myeloid suppressor cell (MySC) numbers are significantly increased in both the spleen and mesenteric lymph nodes after cre induction
• expansion is 5- to 10-fold higher than controls in the spleen and 10- to 20- fold higher in the lymph nodes after cre induction
• when cre expression is only partially induced, significant increase in MySC numbers are still observed
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• Cd11b +Gr+ myeloid suppressor cell (MySC) have an enhanced ability on a per cell basis to suppress allogenic T cells in a mixed lymphocyte reaction
• priming of allogenic T cells by mutant splenocytes is also poor, an effect attributable to the enhanced MySC activity
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• Cd11b+Gr+ myeloid suppressor cell (MySC) numbers are significantly increased in both the spleen and mesenteric lymph nodes after cre induction
• expansion is 5- to 10-fold higher than controls in the spleen and 10- to 20- fold higher in the lymph nodes after cre induction
• when cre expression is only partially induced, significant increase in MySC numbers are still observed
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• Cd11b +Gr+ myeloid suppressor cell (MySC) have an enhanced ability on a per cell basis to suppress allogenic T cells in a mixed lymphocyte reaction
• priming of allogenic T cells by mutant splenocytes is also poor, an effect attributable to the enhanced MySC activity
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in mice in which cre expression is induced, there is a 94% survival rate in irradiated mutant mice receiving wild-type BALB/c bone marrow compared to controls that only had a 57% survival rate
• these mice also have higher weights and have fewer manifestations of GVHD including better skin texture, less fur loss, and more activity
• donor bone marrow engraftment occurred in the mutant mice suggesting the allogenic immune cells present in the mice were being suppressed
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• fetal hemoatopoietic stem cells (HSC) are unable to reconstitute lethally irradiated recipients after pIpC treatment to induce cre expression, indicating cell-autonomous requirement for maintanance and function of fetal HSCs
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit the normal frequency of mature T cells
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• cell-intrinsic reduction of DN3 and DN4 thymocyte proliferation without an increase in apoptosis
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• the percentage of DN3 is increased while the percentage of DN1 and DN4 cells is reduced
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• of mature T cells in the thymus
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| N |
• mice exhibit normal adult hematopoiesis
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• cell-intrinsic reduction of DN3 and DN4 thymocyte proliferation without an increase in apoptosis
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• the percentage of DN3 is increased while the percentage of DN1 and DN4 cells is reduced
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• of mature T cells in the thymus
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• cell-intrinsic reduction of DN3 and DN4 thymocyte proliferation without an increase in apoptosis
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice injected intraperitoneally with poly(I:C) at P8 to induce loss of Pten all die at 20 to 35 days of age
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• mice injected with poly(I:C) at P8 develop myeloproliferative neoplasm with clinical manifestations of Juvenile myelomonocytic leukemia at 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 exhibit reduced total cell numbers in bone marrow at 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 exhibit decreased hemoglobin 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 exhibit increased platelets 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 show a reduction in lymphocytes 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 show decreased B-cell (CD19+) populations in PB and spleen at 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 show decreased T-cell (CD3e+) populations in PB and spleen at 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 exhibit a modest elevation in white blood cells 2-3 weeks post poly(I:C) treatment
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• mice injected with poly(I:C) at P8 show an elevation in granulocytes in bone marrow, blood, and spleen 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 exhibit increased macrophages in bone marrow, blood, and spleen at 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 show an elevation in monocytes in bone marrow, blood, and spleen 2-3 weeks post induction
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• bone marrow of mice injected with poly(I:C) at P8 shows decreased hematopoietic progenitor cells, including LIN-, LIN-Sca1-1-, cKit+, and LIN-Sca1-1+cKit+, are decreased, with less apoptosis
• spleen of mice injected with poly(I:C) at P8 shows an increase in hematopoietic progenitor cells
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• mice injected with poly(I:C) at P8 show substantial monocyte/macrophage and granulocyte infiltration in the spleen at 2-3 weeks post induction
• spleen of mice injected with poly(I:C) at P8 shows an increase in hematopoietic progenitor cells
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• mice injected with poly(I:C) at P8 exhibit increased spleen size
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• mice injected with poly(I:C) at P8 exhibit increased spleen weight
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• mice injected with poly(I:C) at P8 show a reduction in lymphocytes 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 show decreased B-cell (CD19+) populations in PB and spleen at 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 show decreased T-cell (CD3e+) populations in PB and spleen at 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 exhibit a modest elevation in white blood cells 2-3 weeks post poly(I:C) treatment
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• mice injected with poly(I:C) at P8 show an elevation in granulocytes in bone marrow, blood, and spleen 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 exhibit increased macrophages in bone marrow, blood, and spleen at 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 show an elevation in monocytes in bone marrow, blood, and spleen 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 show substantial monocyte/macrophage and granulocyte infiltration in the spleen at 2-3 weeks post induction
• spleen of mice injected with poly(I:C) at P8 shows an increase in hematopoietic progenitor cells
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• mice injected with poly(I:C) at P8 exhibit increased spleen size
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• mice injected with poly(I:C) at P8 exhibit increased spleen weight
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• mice injected with poly(I:C) at P8 show substantial monocyte/macrophage infiltration in the liver at 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 exhibit increased liver size
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• mice injected with poly(I:C) at P8 exhibit increased liver weight
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• mice injected with poly(I:C) at P8 develop myeloproliferative neoplasm with clinical manifestations of Juvenile myelomonocytic leukemia at 2-3 weeks post induction
• recipient mice transplanted with bone marrow nucleated cells from mutants develop an indolent myelodysplastic syndrome or myeloproliferative neoplasm by 8 weeks posttransplantation
• mice injected with poly(I:C) at 6 weeks of age develop a transient myeloproliferative neoplasm after 3 weeks post induction and 1/7 transform to T-ALL
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• mice injected with poly(I:C) at 6 weeks of age develop a transient myeloproliferative neoplasm after 3 weeks post induction and 1/7 transform to T-ALL
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• mice injected with poly(I:C) at P8 show substantial monocyte/macrophage infiltration in the spleens, livers, and lungs at 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 show increases in monocytes/macrophages and granulocytes in the bone marrow at 2-3 weeks post induction
• bone marrow of mice injected with poly(I:C) at P8 shows decreased hematopoietic progenitor cells, including LIN-, LIN-Sca1-1-, cKit+, and LIN-Sca1-1+cKit+, are decreased, with less apoptosis
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• mice injected with poly(I:C) at P8 exhibit increased liver size
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• mice injected with poly(I:C) at P8 exhibit increased liver weight
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• mice injected with poly(I:C) at P8 exhibit increased spleen size
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• mice injected with poly(I:C) at P8 exhibit increased spleen weight
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| juvenile myelomonocytic leukemia | DOID:0050458 |
OMIM:607785 |
J:232645 | |
|
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• median survival of poly(I:C) injected mice at P8 is 35 days
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• mice injected with poly(I:C) at P8 exhibit increased spleen size
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• mice injected with poly(I:C) at P8 exhibit increased spleen weight
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• mice injected with poly(I:C) at P8 show an elevation in granulocytes 2-3 weeks post induction
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• mice injected with poly(I:C) at P8 exhibit increased platelets 2-3 weeks post induction, although the level of platelet increase in smaller than in mice also heterozygous for Nf1tm1Fcr
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• mice injected with poly(I:C) at P8 show a reduction in lymphocytes 2-3 weeks post induction
|
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• mice injected with poly(I:C) at P8 show decreased B-cell (CD19+) populations in PB and spleen at 2-3 weeks post induction
|
|
• mice injected with poly(I:C) at P8 show decreased T-cell (CD3e+) populations in PB and spleen at 2-3 weeks post induction
|
|
• mice injected with poly(I:C) at P8 show substantial macrophage infiltration in the spleens, livers, and lungs at 2-3 weeks post induction
|
|
• mice injected with poly(I:C) at P8 show an elevation in monocytes in the spleens, livers, and lungs at 2-3 weeks post induction
|
|
• mice injected with poly(I:C) at P8 exhibit increased spleen size
|
|
• mice injected with poly(I:C) at P8 exhibit increased spleen weight
|
|
• mice injected with poly(I:C) at P8 show an elevation in granulocytes 2-3 weeks post induction
|
|
• mice injected with poly(I:C) at P8 show a reduction in lymphocytes 2-3 weeks post induction
|
|
• mice injected with poly(I:C) at P8 show decreased B-cell (CD19+) populations in PB and spleen at 2-3 weeks post induction
|
|
• mice injected with poly(I:C) at P8 show decreased T-cell (CD3e+) populations in PB and spleen at 2-3 weeks post induction
|
|
• mice injected with poly(I:C) at P8 show substantial macrophage infiltration in the spleens, livers, and lungs at 2-3 weeks post induction
|
|
• mice injected with poly(I:C) at P8 show an elevation in monocytes in the spleens, livers, and lungs at 2-3 weeks post induction
|
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• mice injected with poly(I:C) at P8 exhibit increased liver size
|
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• mice injected with poly(I:C) at P8 exhibit increased liver weight
|
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• mice injected with poly(I:C) at 6 weeks of age develop a transient myeloproliferative neoplasm after 3 weeks post induction and 5/7 transform to T-ALL
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• mice injected with poly(I:C) at 6 weeks of age develop a transient myeloproliferative neoplasm after 3 weeks post induction and 5/7 transform to T-ALL
|
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• mice injected with poly(I:C) at P8 exhibit increased liver weight
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• mice injected with poly(I:C) at P8 exhibit increased spleen size
|
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• mice injected with poly(I:C) at P8 exhibit increased spleen weight
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• percentage of LSK cells is decreased in G1 and increased in S as compared to controls
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• increase in the proportion of apoptotic hematopoietic stem (LSK) cells
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• erythroid dysplasia
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• decrease in intermediate myeloid progenitors (pre-MEGE, pre-CFUE)
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• myeloid dysplasia
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• appearance of nuclear irregularities and cytoplasmic vacuolization and blebbing of erythroid precursors
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• appearance of hypolobated and hypogranulated neutrophils
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• decreased numbers of B cells in peripheral blood at all stages beginning at pro-B cell number
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• increase in splenic LSK cells 14 weeks after pIpC injection although splenomegaly is not observed
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• leukopenia is observed in bone marrow of lethally irradiated recipient mice 18 weeks post-transplantation (pIpC injection 4 weeks after transplantation)
• anemia is observed 18 weeks post-bone marrow transplantation (pIpC injection 4 weeks after transplantation)
• mean corpuscular volume (MCV) is increased in donor bone marrow post-transplantation
• hemoglobin is decreased in donor bone marrow post-transplantation
• increase in total hematopoietic stem cell (LSK) cell number in non-competitive bone marrow transplantation assay 14 weeks after pIpC injection relative to controls
• increase in restricted hematopoietic progenitor cells (LSK, CD48+, CD150+) in bone marrow transplantation assay 14 weeks after pIpC injection relative to controls
increase in restricted hematopoietic progenitor cells (LSK, CD48+, CD150+) in bone marrow transplantation assay 14 weeks after pIpC injection relative to controls
increase in restricted hematopoietic progenitor cells (LSK, CD48+, CD150+) in bone marrow transplantation assay 14 weeks after pIpC injection relative to controls
• increase in total LSK cell number in bone marrow in competitive bone marrow transplantation assay 14 weeks post-pIpC injection
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• increase in proportion of apoptotic hematopoietic stem (LSK) cells
• percentage of LSK cells is decreased in G1 and increased in S as compared to controls
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• decrease in intermediate myeloid progenitors (pre-MEGE, pre-CFUE)
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• myeloid dysplasia
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• appearance of hypolobated and hypogranulated neutrophils
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• decreased numbers of B cells in peripheral blood at all stages beginning at pro-B cell number
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| myelodysplastic syndrome | DOID:0050908 |
OMIM:614286 |
J:221404 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutants become ill shortly after pIpC treatment and exhibit lethargy, ruffling of fur, and hunched posture and die from leukemia
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• mice treated with pIpC to induce Cre expression exhibit an enlarged thymus
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• 10-fold increase in spleen cellularity after pIpC administration to induce Cre expression
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• increase in blast cell frequency after pIpC administration to induce Cre expression
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• mice treated with polyinosine-polycytidine (pIpC) to induce Cre expression exhibit extramedullary hematopoiesis, with prominent expansion in the number of immature myeloid cells
• mice develop myeloproliferative disease shortly after pIpC administration to induce Cre expression with complete effacement of the splenic architecture
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• reduction in bone marrow cellularity after pIpC administration to induce Cre expression
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• mice treated with pIpC to induce Cre expression exhibit an increase in hematopoietic stem cell proliferation but become depleted, most likely due to inhibition of self-renewal as no increase in cell death was observed
• mutants maintained on rapamycin after pIpC treatment do not exhibit expansion of hematopoietic stem cells
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• mice treated with pIpC to induce Cre expression exhibit an enlarged thymus
|
|
• 10-fold increase in spleen cellularity after pIpC administration to induce Cre expression
|
|
• within 4-6 weeks after pIpC treatment, most mutants progress to leukemia, including acute myeloid leukemia and acute lymphoblastic leukemia
• mutants maintained on rapamycin after pIpC treatment do not develop leukemia
|
|
• seen in mutants within 4-6 weeks after pIpC treatment
|
|
• seen in mutants within 4-6 weeks after pIpC treatment
|
|
• mice treated with pIpC to induce Cre expression exhibit an enlarged thymus
|
|
• 10-fold increase in spleen cellularity after pIpC administration to induce Cre expression
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• irradiated wild-type mice reconstituted with Notch1/2-null bone marrow progenitors analyzed at 8 weeks show block at earliest intrathymic precursor stage; immature B cells develop in the thymus recapitulating the Notch1-null phenotype
• cultured double-null hematopoietic stem cells, HSCs do not develop into T cell progenitors after 10 days
|
|
• cultured double null HSCs display a block at the double negative 1 stage
|
|
• irradiated wild-type mice reconstituted with Notch1/2-null bone marrow progenitors analyzed at 8 weeks show block at earliest intrathymic precursor stage; immature B cells develop in the thymus recapitulating the Notch1-null phenotype
• cultured double-null hematopoietic stem cells, HSCs do not develop into T cell progenitors after 10 days
|
|
• cultured double null HSCs display a block at the double negative 1 stage
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die at 11 weeks after treatment with pIpC with splenomegalia and hepatomegalia
|
| N |
• the deficits in splenocytes, bone marrow cells and pre-B cells observed in Rnf2tm1Mvi/Rnf2tm1Mvi Tg(Mx1-cre)1Cgn mice treated with pIpC at 6 to 12 weeks is not observed
|
|
• following treatment with pIpC at 6 to 12 weeks, mice exhibit an increase in myeloid colony forming units relative to wild-type mice
|
|
• following treatment with pIpC, mice develop lymphomas at an earlier age of onset compared to in Cdkn2atm1Rdp homozygotes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• poly(I:C)-treated mice show defects in platelet accumulation at sites of injury laser-induced cremaster arteriole injury
|
|
• poly(I:C)-treated mice show defects in platelet accumulation and fibrin deposition at sites of laser-induced cremaster arteriole injury
|
| N |
• poly(I:C)-treated mice exhibit normal blood counts and platelet counts are comparable to controls although slightly lower after poly(I:C) and platelet size is comparable to controls
|
|
• poly(I:C)-treated mice show defects in platelet accumulation at sites of injury laser-induced cremaster arteriole injury
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• slightly eleveated levels of ALT are found in the sera after Cre-induction but not to the degree of conditional knockouts with wild-type Sqstm1 alleles
|
|
• high levels of ALP are found in the sera after Cre-induction but not to the degree of conditional knockouts with wild-type Sqstm1 alleles
|
|
• slightly elevated levels of AST are found in the sera after Cre-induction but not to the degree of conditional knockouts with wild-type Sqstm1 alleles
|
|
• the cytoplasmic inclusion bodies containing ubiquitinated proteins that are associated with Atg7 conditional liver knockout mice are almost completely absent in these mice
|
|
• liver function is slightly decreased after Cre-induction but not to the degree of conditional knockouts with wild-type Sqstm1 alleles
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• homozygous mutant mice exhibit normal hematopoiesis, including normal hematopoietic stem cell self-renewal and differentiation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• homozygous mutant mice exhibit normal hematopoiesis, including normal hematopoietic stem cell self-renewal and differentiation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• few osteoclasts are present in the tibia after polyI:C treatment
• however, osteoblast numbers are similar to control
|
|
• percentage of bone area to total marrow space in long bones is 1.9 fold that of controls
|
|
• following polyI:C treatment
|
|
• decreased trabecular spacing in the tibia after polyI:C treatment
|
|
• following polyI:C treatment
• abundance of bone and cartilage trabeculae following polyI:C treatment
|
|
• following polyI:C treatment
|
|
• following polyI:C treatment
|
|
• following polyI:C treatment
|
|
• few osteoclasts are present in the tibia after polyI:C treatment
• however, osteoblast numbers are similar to control
|
|
• few osteoclasts are present in the tibia after polyI:C treatment
• however, osteoblast numbers are similar to control
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pIpC-treated mice exhibit depletion of early T cell progenitors in the thymus
|
|
• in the bone marrow of pIpC-treated mice
|
|
• less functionally competent than in cells from pIpC-treated mice Fbxw7tm2Iaai/Fbxw7+ Tg(Mx1-cre)1Cgn mice
|
|
• pIpC-treated mice exhibit depletion of early T cell progenitors in the thymus
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• normal hematopoiesis and hematopoietic stem cell self renewal and regenerative ability in spite of an increased hematopoietic stem cell proliferative capacity observed in vitro
|
|
• hematopoietic stem cells from polyIC-induced mice show increased proliferation recruitment when cultured as single cells under low stimulatory conditions in vitro
|
|
• hematopoietic stem cells from polyIC-induced mice show increased proliferation recruitment when cultured as single cells under low stimulatory conditions in vitro
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• absence of marginal zone B cells
• other populations of B cells as well as T cells in the spleen are normal, and B and T cell populations in the lymph nodes are normal
|
|
• absence of marginal zone B cells
• other populations of B cells as well as T cells in the spleen are normal, and B and T cell populations in the lymph nodes are normal
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• of pre-T cells as in Ccnd3tm1Pisc homozygotes
|
|
• not as severe as in pIpC-treated mice as in Ccnd3tm1Pisc homozygotes
|
|
• as in Ccnd3tm1Pisc homozygotes
|
|
• of pre-T cells as in Ccnd3tm1Pisc homozygotes
|
|
• not as severe as in pIpC-treated mice as in Ccnd3tm1Pisc homozygotes
|
|
• as in Ccnd3tm1Pisc homozygotes
|
|
• not as severe as in pIpC-treated mice as in Ccnd3tm1Pisc homozygotes
|
|
• of pre-T cells as in Ccnd3tm1Pisc homozygotes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• some mutants injected with interferon-alpha at days 3, 6, 9, and 11 after birth to induce partial gene disruption die for unknown reasons
|
|
• mutants injected with interferon-alpha to induce partial gene disruption show reduced body weight after two weeks post injection
|
|
• mutants injected with interferon-alpha to induce partial gene disruption show transient growth retardation
|
|
• thymus architecture is abnormal in mutants injected with interferon-alpha to induce partial gene disruption, such that medullary and cortical regions cannot be distinguished
thymic dentritic cells are reduced
|
|
• mutants injected with interferon-alpha exhibit an accumulation of B cells in the thymus that differ from normally occurring thymic B cells and resemble immature B cells normally found in the bone marrow
(J:55400)
• more thymic B cells are present than in control mice and they exhibit varying expression levels of IgM and B220 unlike in Dll4tm1Frad homozygous control mice
(J:143472)
|
|
• mutants injected with interferon-alpha to induce partial gene disruption have a small thymus
|
|
• mutants injected with interferon-alpha to induce partial gene disruption show a 5-fold reduction in thymocyte number
|
|
• hematopoietic stem cells do not develop in to B cells after 18 days in culture
|
|
• the absolute numbers of immature B cells in the thymus are increased 30-fold compared to in Dll4tm1Frad homozygous control mice
|
|
• mutants injected with interferon-alpha to induce partial gene disruption show abnormal T cell maturation and show a block at or before the most immature T cell stage, as most triple-negative (CD4-CD8-TCR-) thymoctyes are CD44+CD25-
(J:55400)
• irradiated wild-type mice reconstituted with Notch1-null bone marrow progenitors analyzed at 8 weeks show block at earliest intrathymic precursor stage; immature B cells develop in the thymus
(J:125373)
• >90% of Notch1-null HSCs cultured on stromal cells for 28 days are blocked in the double negative compartment and do not progress from double negative to double positive
(J:125373)
|
|
• TCRgamma/delta+ double-negative thymocytes from mutants injected with interferon-alpha are decreased 10-fold
|
|
• thymocytes from mutants injected with interferon-alpha show a 9-fold reduction in double-positive cells
|
|
• thymocytes from mutants injected with interferon-alpha show a 5-fold reduction in CD4+ single-positive cells
|
|
• thymocytes from mutants injected with interferon-alpha show a 4.4-fold reduction in CD8+ single-positive cells
|
|
• immature single-positive thymocytes from mutants injected with interferon-alpha are decreased 13-fold
|
| N |
• mutants exhibit normal hematopoietic stem cell self-renewal and differentiation
|
|
• thymus architecture is abnormal in mutants injected with interferon-alpha to induce partial gene disruption, such that medullary and cortical regions cannot be distinguished
thymic dentritic cells are reduced
|
|
• mutants injected with interferon-alpha exhibit an accumulation of B cells in the thymus that differ from normally occurring thymic B cells and resemble immature B cells normally found in the bone marrow
(J:55400)
• more thymic B cells are present than in control mice and they exhibit varying expression levels of IgM and B220 unlike in Dll4tm1Frad homozygous control mice
(J:143472)
|
|
• mutants injected with interferon-alpha to induce partial gene disruption have a small thymus
|
|
• mutants injected with interferon-alpha to induce partial gene disruption show a 5-fold reduction in thymocyte number
|
|
• hematopoietic stem cells do not develop in to B cells after 18 days in culture
|
|
• the absolute numbers of immature B cells in the thymus are increased 30-fold compared to in Dll4tm1Frad homozygous control mice
|
|
• mutants injected with interferon-alpha to induce partial gene disruption show abnormal T cell maturation and show a block at or before the most immature T cell stage, as most triple-negative (CD4-CD8-TCR-) thymoctyes are CD44+CD25-
(J:55400)
• irradiated wild-type mice reconstituted with Notch1-null bone marrow progenitors analyzed at 8 weeks show block at earliest intrathymic precursor stage; immature B cells develop in the thymus
(J:125373)
• >90% of Notch1-null HSCs cultured on stromal cells for 28 days are blocked in the double negative compartment and do not progress from double negative to double positive
(J:125373)
|
|
• TCRgamma/delta+ double-negative thymocytes from mutants injected with interferon-alpha are decreased 10-fold
|
|
• thymocytes from mutants injected with interferon-alpha show a 9-fold reduction in double-positive cells
|
|
• thymocytes from mutants injected with interferon-alpha show a 5-fold reduction in CD4+ single-positive cells
|
|
• thymocytes from mutants injected with interferon-alpha show a 4.4-fold reduction in CD8+ single-positive cells
|
|
• immature single-positive thymocytes from mutants injected with interferon-alpha are decreased 13-fold
|
|
• thymus architecture is abnormal in mutants injected with interferon-alpha to induce partial gene disruption, such that medullary and cortical regions cannot be distinguished
thymic dentritic cells are reduced
|
|
• mutants injected with interferon-alpha exhibit an accumulation of B cells in the thymus that differ from normally occurring thymic B cells and resemble immature B cells normally found in the bone marrow
(J:55400)
• more thymic B cells are present than in control mice and they exhibit varying expression levels of IgM and B220 unlike in Dll4tm1Frad homozygous control mice
(J:143472)
|
|
• mutants injected with interferon-alpha to induce partial gene disruption have a small thymus
|
|
• mutants injected with interferon-alpha to induce partial gene disruption show a 5-fold reduction in thymocyte number
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• many cadmium induced changes in liver gene expression seen in controls are not seen in mutants
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• most mice die 7-10 days after final dose of the immunostimulant dsRNA poly(I:C) as compared to controls
• lethality is a result severe anemia
|
|
• hematopoietic stem and progenitor cell populations are distorted following final dose of poly(I:C)
|
|
• increase in numbers of bipotential granulocytic/moncytic precursor cells following final dose of poly(I:C)
• accumulation of immature myeloid cells
|
|
• decrease in numbers of myeloid progenitors (Sca-1- cKit+, LS-K+) after final dose of poly(I:C)
|
|
• Gr1high Mac1+ granulocytes are almost absent from bone marrow after final dose of poly(I:C)
|
|
• loss of mature neutrophils following final dose of poly(I:C)
|
|
• decrease in numbers of hematopoietic stem cells and multipotent progenitors (Sca-1+ cKit+, LS+K+) 1 week after final dose of poly(I:C)
|
|
• following final dose of poly(I:C)
|
|
• four fold increase in long term repopulating hematopoietic stem cell (LT-HSC) population (lin- CD150+ CD48- Sca-1+ c-Kit+) found in recombined cells
• immunophenotypic LT-HSC population exhibits 2-fold proliferation, but unaltered apoptosis levels
|
|
• Gr1high Mac1+ granulocytes are almost absent from bone marrow after final dose of poly(I:C)
|
|
• loss of mature neutrophils following final dose of poly(I:C)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• do not survive more than 20 weeks after induction of cre mediated recombination
|
|
• significant reduction of the lymphoid-biased multipotential progenitor population (L-MPP) after induction of cre mediated recombination
• striking increase in the absolute numbers of both bone marrow and spleen granulocyte/monocyte progenitors cells after induction of cre mediated recombination
• decrease of the megakaryocyte?erythrocyte progenitor population after induction of cre mediated recombination
• progenitor cells display an increase in their self-renewal capacity after induction of cre mediated recombination
|
|
• striking peripheral blood leukocytosis after induction of cre mediated recombination
|
|
• striking peripheral blood monocytosis after induction of cre mediated recombination
• increase in monocyte numbers in the bone marrow and liver after induction of cre mediated recombination
|
|
• de-repression of an extended myeloid-specific program in LSK cells
|
|
• increase in LSK numbers after induction of cre mediated recombination
|
|
• expansion of the red pulp with diffuse infiltration by myeloid and monocytic cells after induction of cre mediated recombination
|
|
• after induction of cre mediated recombination
|
|
• expansion of the red pulp after induction of cre mediated recombination
|
|
• similarity to chronic myelomonocytic leukemia after induction of cre mediated recombination
|
|
• striking peripheral blood leukocytosis after induction of cre mediated recombination
|
|
• striking peripheral blood monocytosis after induction of cre mediated recombination
• increase in monocyte numbers in the bone marrow and liver after induction of cre mediated recombination
|
|
• expansion of the red pulp with diffuse infiltration by myeloid and monocytic cells after induction of cre mediated recombination
|
|
• after induction of cre mediated recombination
|
|
• expansion of the red pulp after induction of cre mediated recombination
|
|
• after induction of cre mediated recombination
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| chronic myeloid leukemia | DOID:8552 |
OMIM:608232 |
J:172442 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• abnormal histone methylation and reversal of leukemia-associated epigenetic profiles
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in competitive repopulation assays, mice transplanted with bone marrow from pIpC-treated mice exhibit impaired erythropoiesis compared with mice transplanted with control bone marrow
|
|
• in competitive repopulation assays, mice transplanted with bone marrow from pIpC-treated mice exhibit impaired leukopoiesis compared with mice transplanted with control bone marrow
|
|
• in competitive repopulation assays, mice transplanted with bone marrow from pIpC-treated mice exhibit impaired leukopoiesis compared with mice transplanted with control bone marrow
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• by 35 weeks after induction of Cre expression (and thus Bax deletion) in the adult, 78% of mutants die compared to 5% of wild-type
|
|
• thymic T cell development is perturbed after poly(I:C) injection
|
|
• accumulation of white blood cells after injection of poly(I:C) to induce Cre expression in adult
|
|
• exhibit accumulation of B cells in the spleen and bone marrow 6 weeks after poly(I:C) injection to induce Cre expression
|
|
• develop autoimmune disease after poly(I:C) injection to induce Bax deletion in the adult
|
|
• show elevated serum antinuclear antibodies and anti-dsDNA antibody after 30 weeks of poly(I:C) injection to induce Bax deletion in the adult
|
|
• develops after poly(I:C) injection to induce Bax deletion in the adult
|
|
• thymic T cell development is perturbed after poly(I:C) injection
|
|
• accumulation of white blood cells after injection of poly(I:C) to induce Cre expression in adult
|
|
• exhibit accumulation of B cells in the spleen and bone marrow 6 weeks after poly(I:C) injection to induce Cre expression
|
|
• develops after poly(I:C) injection to induce Bax deletion in the adult
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in pIpC-treated mice with the same timing as in pIpC-treated Nf1tm1Par/Nf1tm1Par Tg(Mx1-cre)1Cgn mice
|
|
• pIpC-treated mice develop myeloproliferative disorder with anemia unlike wild-type mice that is similar to in pIpC-treated Nf1tm1Par/Nf1tm1Par Tg(Mx1-cre)1Cgn mice
|
|
• pIpC-treated mice develop myeloproliferative disorder with anemia unlike wild-type mice that is similar to in pIpC-treated Nf1tm1Par/Nf1tm1Par Tg(Mx1-cre)1Cgn mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• half of the mature B cells in the spleen are absent
• only a small number of mature B cells are lost upon short-term inactivation of Pax5
• polyinosine-polycystosine (pIpC)-treated mice lack IgD+B220hi cells
|
|
• half of the mature B cells in the spleen are absent
• only a small number of mature B cells are lost upon short-term inactivation of Pax5
• polyinosine-polycystosine (pIpC)-treated mice lack IgD+B220hi cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice injected with pIpC to induce Pten deletion have an enlarged thymus
|
|
• mice injected with pIpC to induce Pten deletion have an enlarged spleen
|
|
• mice injected with pIpC to induce Pten deletion, develop myeloproliferative disease and T-cell acute lymphoblastic leukemia, but at a slower rate than in single Pten mutants
|
|
• mean survival time of mice injected with pIpC to induce Pten deletion is 46 days
|
|
• mice injected with pIpC to induce Pten deletion have an enlarged thymus
|
|
• mice injected with pIpC to induce Pten deletion have an enlarged spleen
|
|
• mice injected with pIpC to induce Pten deletion have an enlarged thymus
|
|
• mice injected with pIpC to induce Pten deletion have an enlarged spleen
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in pIpC-treated mice similar to in pIpC-treated Krastm4Tyj Tg(Mx1-cre)1Cgn mice
|
|
• pIpC-treated mice develop myeloproliferative disorder with anemia unlike wild-type mice that is similar to in pIpC-treated Krastm4Tyj Tg(Mx1-cre)1Cgn mice
|
|
• bone marrow cells from pIpC-treated mice spontaneous form colony forming units-granulocyte and macrophage (CFU-GM) in the absence of cytokines unlike wild-type cells
|
|
• in pIpC-treated mice similar to in pIpC-treated Krastm4Tyj Tg(Mx1-cre)1Cgn mice
|
|
• pIpC-treated mice develop myeloproliferative disorder with anemia unlike wild-type mice that is similar to in pIpC-treated Krastm4Tyj Tg(Mx1-cre)1Cgn mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in lethally irradiated mice reconstituted with pIpC-treated bone marrow cells
|
|
• in lethally irradiated mice reconstituted with pIpC-treated bone marrow cells, red blood cells contain Heinz bodies and hemoglobin precipitates unlike in cells from mice reconstituted with untreated bone marrow
|
|
• erythroid precursor maturation is severely impaired with erythroid hyperplasia in bone marrow and spleen in lethally irradiated mice reconstituted with pIpC-treated bone marrow cells compared to when untreated bone marrow is used
|
|
• in lethally irradiated mice reconstituted with pIpC-treated bone marrow cells
|
|
• in lethally irradiated mice reconstituted with pIpC-treated bone marrow cells
|
|
• in lethally irradiated mice reconstituted with pIpC-treated bone marrow cells
|
|
• in lethally irradiated mice reconstituted with pIpC-treated bone marrow cells
|
|
• in lethally irradiated mice reconstituted with pIpC-treated bone marrow cells
|
|
• in lethally irradiated mice reconstituted with pIpC-treated bone marrow cells
|
|
• in lethally irradiated mice reconstituted with pIpC-treated bone marrow cells
|
|
• in lethally irradiated mice reconstituted with pIpC-treated bone marrow cells
|
|
• in lethally irradiated mice reconstituted with pIpC-treated bone marrow cells
|
|
• in lethally irradiated mice reconstituted with pIpC-treated bone marrow cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• myeloproliferative disease
|
|
• massive invasion of myeloid cells
|
|
• massive invasion of myeloid cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increase in the granulocyte/monocyte progenitors cell population
|
|
• increase in the granulocyte/monocyte progenitors cell population
|
|
• massive invasion of myeloid cells
|
|
• similarity to chronic myelomonocytic leukemia
|
|
• massive invasion of myeloid cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increased TNF and IL-6 production by peritoneal macrophages stimulated by LPS and IFN-gamma, relative to those of wild-type
|
|
• increased IL-6 production by peritoneal macrophages stimulated by LPS and IFN-gamma, relative to those of wild-type
|
|
• increased TNF production by peritoneal macrophages stimulated by LPS and IFN-gamma, relative to those of wild-type
|
|
• increased TNF and IL-6 production by peritoneal macrophages stimulated by LPS and IFN-gamma, relative to those of wild-type
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• conditional mice show no liver phenotype
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• wheni injected with poly(I:C) to induce cre expression, mutants become moribund and die within 2-3 weeks
|
|
• after cre induction, mutants have ~25% of control cell numbers in thymus
|
|
• a block at the DN1-DN2 transition is found
|
|
• myeloid cells are almost totally absent in induced mutants
|
|
• induced mutants have fewer leukocytes
|
|
• the double negative compartment of thymic T cells is relatively decreased relative to CD4 and CD8 double positive and single positive T cells
|
|
• after cre induction, mice show a loss of granulocytic cells
|
|
• after cre induction, mutants have ~25% of control cell numbers in thymus
|
|
• a block at the DN1-DN2 transition is found
|
|
• myeloid cells are almost totally absent in induced mutants
|
|
• after cre induction, mutants have ~25% of control bone marrow cell numbers
|
|
• bone marrow shows abnormal presence of immature erythroid cells in induced mutants
|
|
• peripheral blood from induced mutants is pale and has reduced red blood cell counts
|
|
• hemoglobin concentration in peripheral blood of induced mutants is reduced
|
|
• platelet count in induced mutants is reduced
|
|
• induced mutants have fewer leukocytes
|
|
• the double negative compartment of thymic T cells is relatively decreased relative to CD4 and CD8 double positive and single positive T cells
|
|
• after cre induction, mice show a loss of granulocytic cells
|
|
• after cre induction, mutants have ~25% of control cell numbers in thymus
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit a normal lifespan and causes of death
|
| N |
• MOL4070LTR-induced leukemia is the same as in similarly treated wild-type mice
|
| N |
• mice exhibit normal blood counts
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following induction with poly(I:C)
|
|
• following induction with poly(I:C), hemorrhaging in the heart leads to muscle ischemia/necrosis, neutrophil infiltrates and early granulation tissue, and disruption of muscle architecture by amorphous plasma and matrix proteins
|
|
• aged uninduced mice develop hemosiderin depositions and cardiac fibrosis unlike wild-type mice
|
|
• following induction with poly(I:C), nearly all mice exhibit cardiac hemorrhaging with some hemorrhaging in the pleural cavity (in 46% of mice), intracranial cavity (in 46% of mice), or focally within the skeletal muscle (in 18% of mice) unlike in wild-type mice
• however, without induction with poly(I:C) no hemorrhaging is observed
|
|
• following induction with poly(I:C), 46% of mice exhibit some hemorrhaging in the pleural cavity
|
|
• hemorrhaging is occasionally observed in the testes following induction with poly(I:C)
|
|
• hemorrhaging is occasionally observed in the bowels following induction with poly(I:C)
|
|
• nearly all mice exhibit cardiac hemorrhaging following induction with poly(I:C)
• hemorrhaging in the heart leads to muscle ischemia/necrosis, neutrophil infiltrates and early granulation tissue, and disruption of muscle architecture by amorphous plasma and matrix proteins
|
|
• following induction with poly(I:C), 46% of mice exhibit intracranial hemorrhaging; bleeding is often dural based with ventricular and parenchymal hemorrhaging occurring and parenchymal bleeding encountered in the medulla, cerebellum and hippocampus
|
|
• following induction with poly(I:C)
|
|
• following induction with poly(I:C), 18% of mice exhibit focal hemorrhaging within skeletal muscle
|
|
• hemorrhaging is occasionally observed in the spinal canal following induction with poly(I:C)
|
|
• hemorrhaging is occasionally observed in the skin following induction with poly(I:C)
|
|
• clotting time is modestly increased compared to in wild-type mice
• following induction with poly(I:C), clotting time is severely increased compared to in wild-type mice
• however, platelet counts and fibrinogen amounts are normal, and treatment with prothrombin restores normal clotting times
|
|
• following induction with poly(I:C)
|
|
• following induction with poly(I:C), 46% of mice exhibit intracranial hemorrhaging; bleeding is often dural based with ventricular and parenchymal hemorrhaging occurring and parenchymal bleeding encountered in the medulla, cerebellum and hippocampus
|
|
• following induction with poly(I:C)
|
|
• hemorrhaging is occasionally observed in the spinal canal following induction with poly(I:C)
|
|
• hemorrhaging is occasionally observed in the skin following induction with poly(I:C)
|
|
• hemorrhaging is occasionally observed in the testes following induction with poly(I:C)
|
|
• following induction with poly(I:C), 46% of mice exhibit some hemorrhaging in the pleural cavity
|
|
• hemorrhaging is occasionally observed in the bowels following induction with poly(I:C)
|
|
• following induction with poly(I:C), 18% of mice exhibit focal hemorrhaging within skeletal muscle
|
|
• hemorrhaging is occasionally observed in the testes following induction with poly(I:C)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• rapid decline in survival with complete lethality observed at 2 weeks after polyIC induction, associated with a significant decrease in peripheral blood cells
|
|
• complete hematopoietic failure on day 8 after first polyIC injection
|
|
• on day 8 after first polyIC injection, surviving mice show massive loss of bone marrow cellularity, involving coordinated loss of myeloid (Mac-1+) and lymphoid (B220+) cells
|
|
• complete loss of Lin-Sca-1+c-Kit+ (LSK) hematopoietic stem cells in the bone marrow on day 8 after first polyIC injection
|
|
• death at 2 weeks after polyIC induction is associated with pancytopenia
|
|
• competitive repopulation experiments revealed loss of hematopoietic stem cells through apoptosis
|
|
• bone marrow failure characterized by apoptotic loss of hematopoietic stem cells on day 8 after first polyIC injection
|
|
• bone marrow failure characterized by apoptotic loss of hematopoietic stem cells on day 8 after first polyIC injection
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• thymus is large and contains both double positive and CD4+ cells
|
|
• a population of peripheral lymphocytes are produced which are CD4+ but with a 2-3 fold reduction in surface expression of CD4
|
|
• CD8 single positive cells are absent
|
|
• thymus is large and contains both double positive and CD4+ cells
|
|
• a population of peripheral lymphocytes are produced which are CD4+ but with a 2-3 fold reduction in surface expression of CD4
|
|
• CD8 single positive cells are absent
|
|
• thymus is large and contains both double positive and CD4+ cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 2-3 weeks after induction of cre expression with pI-pC, number of HSCs in bone marrow is decreased with loss of CMPs, GMPs and mature myeloid cells while MEPs are increased
• by 6 weeks, numbers of CLPs, CMPs, and GMPs begin to recover
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• about 2 weeks after p(I)p(C) injections an almost complete block in B cell development is seen
|
|
• about 2 weeks after p(I)p(C) injections most of the B cells are lost from the spleen and lymph nodes
• marginal zone B cells were not affected probably as a result of replenishment from cells that escaped cre mediated recombination
|
|
• in the spleen almost all immature spleen cells are missing
|
|
• about 2 weeks after p(I)p(C) injections an almost complete block in B cell development is seen
|
|
• about 2 weeks after p(I)p(C) injections most of the B cells are lost from the spleen and lymph nodes
• marginal zone B cells were not affected probably as a result of replenishment from cells that escaped cre mediated recombination
|
|
• in the spleen almost all immature spleen cells are missing
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Disfigured ears, abdominal alopecia and scales on feet in Supv3l1tm2Jkl/Supv3l1tm2Jkl Tg(Mx1-cre)1Cgn/0 mice
|
• some mice become moribund at 4 weeks of age while others live up to 10 weeks
|
|
• in the red pulp of the liver
|
|
• in the red pulp of the liver
|
|
• 50% of wild-type at 4 weeks
|
|
• at weaning, mice exhibit slower growth than wild-type mice
|
|
• in moribund mice
|
|
• mice exhibit a thickened interstitium with infiltration by inflammatory cells and occasionally foamy macrophages
|
|
• in moribund mice
|
|
• the number of sebaceous glands is decreased compared to in wild-type mice
|
|
• dilated vessels are found in the dermal layer of cells of the ear unlike in wild-type mice
|
|
• locomotor functions fail in moribund mice
|
|
• at weaning mice have flattened and disfigured ears compared to in wild-type mice
|
|
• in the red pulp of the liver
|
|
• in the red pulp of the liver
|
|
• in the red pulp of the liver
|
|
• the number of sebaceous glands is decreased compared to in wild-type mice
|
|
• at weaning, mice exhibit abnormal appearance and density of coat hairs compared to in wild-type mice
|
|
• some mice exhibit mild dermal acute inflammatory infiltrate unlike in wild-type mice
• the dermal layer is atrophic unlike in wild-type mice
|
|
• dyskeratosis (apoptosis) is increased in the basal cell layer and mid-epidermis compared to in wild-type mice
|
|
• severe
|
|
• on the dorsal and abdominal skin
|
|
• after 6 weeks mice exhibit scaly dorsal and abdominal skin, feet, tail, and ears
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 2 weeks after p(I)p(C) injections an almost complete block in B cell development is seen
|
|
• 2 weeks after p(I)p(C) injections two thirds of the B cells are lost from the spleen, blood, lymph nodes, liver, and lung
• mature follicular B cells are more affected than marginal zone B cells
|
|
• in the spleen almost all immature spleen cells are missing
|
|
• 2 weeks after p(I)p(C) injections an almost complete block in B cell development is seen
|
|
• 2 weeks after p(I)p(C) injections two thirds of the B cells are lost from the spleen, blood, lymph nodes, liver, and lung
• mature follicular B cells are more affected than marginal zone B cells
|
|
• in the spleen almost all immature spleen cells are missing
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice induced with interferon gamma exhibited similar responses to starvation as controls, although it was noted that 40S ribosomes were absent and 60S ribosomes were increased in number in mutant liver recovering from starvation
|
|
• expression of cell cycle markers such as cyclin E and cyclin A were not seen in mutant hepatocytes suggesting a block in cell cycle progression
|
|
• after partial hepatectomy, mutant liver failed to regenerate after 10 days; histopathology revealed no evidence of regenerative or pathological processes in mutant liver; expression of cell cycle markers such as cyclin E and cyclin A were not seen in mutants suggesting a block in cell cycle progression
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mean survival of pIpC-treated mice is 99 days compared with 150 days for Gt(Rosa)26Sortm4(CAG-hsb5)Nki Gt(Rosa)26Sor+ Tg(Mx1-cre)1Cgn TgTn(pb-sb-GrOnc)#aGsva control mice
|
|
• all mice develop aggressive leukemia and/or lymphoma within a year of pIpC induction
|
|
• in pIpC-treated mice
|
|
• all mice develop aggressive leukemia and/or lymphoma within a year of pIpC induction
• however, pIpC-treated mice do not develop T cell lymphomas unlike in control mice
|
|
• in some pIpC-treated mice
|
|
• angiosarcoma in some pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice injected with poly(I)poly(C) show a decrease in numbers of pre-B (IgM-B220+CD43-) and immature B cells (IgM+B220int), indicating impaired pro-B to pre-B cell transition
|
|
• mice injected with poly(I)poly(C) show a decrease in numbers of immature B cells (IgM+B220int)
|
|
• recombination of VHJ558 segments is reduced to 25% of the control
|
|
• pro-B cells do not form a well-defined population of B220int, intracellular mu+ cells and the overall frequency of B220+, intracellular mu+ cells is reduced to 30%
|
|
• mice injected with poly(I)poly(C) show a decrease in numbers of pre-B (IgM-B220+CD43-)
|
|
• mice injected with poly(I)poly(C) show a decrease in numbers of pre-B (IgM-B220+CD43-) and immature B cells (IgM+B220int), indicating impaired pro-B to pre-B cell transition
|
|
• mice injected with poly(I)poly(C) show a decrease in numbers of immature B cells (IgM+B220int)
|
|
• recombination of VHJ558 segments is reduced to 25% of the control
|
|
• pro-B cells do not form a well-defined population of B220int, intracellular mu+ cells and the overall frequency of B220+, intracellular mu+ cells is reduced to 30%
|
|
• mice injected with poly(I)poly(C) show a decrease in numbers of pre-B (IgM-B220+CD43-)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• pIpC-treated mice have a normal lifespan
|
|
• mice treated with pIpC and Moloney murine leukemia virus (MMLV) exhibit increased morbidity and mortality with all mice dying by 6 months of age unlike with similarly treated Tcf3tm1(TCF3/HLF)Homy heterozygotes
|
| N |
• pIpC-treated mice exhibit no abnormalities in peripheral blood
|
|
• pIpC-treated mice exhibit an increase in B cell precursors in the bone marrow compared with similarly treated Tcf3tm1(TCF3/HLF)Homy heterozygotes
|
|
• pIpC-treated mice exhibit an increase in B cell precursors in the bone marrow compared with similarly treated Tcf3tm1(TCF3/HLF)Homy heterozygotes
|
|
• mice treated with pIpC and Moloney murine leukemia virus (MMLV) exhibit increased morbidity and mortality with all mice dying by 6 months of age unlike with similarly treated Tcf3tm1(TCF3/HLF)Homy heterozygotes
• mice treated with pIpC and MMLV develop only acute B-progenitor and lineage marker negative leukemias as early as 2.6 months compared with similarly treated Tcf3tm1(TCF3/HLF)Homy heterozygotes that develop T cell leukemias at 4 to 6 months
|
|
• pIpC-treated and Moloney murine leukemia virus (MMLV)-exposed mice develop microthrombi
|
|
• pIpC-treated mice exhibit an increase in B cell precursors in the bone marrow compared with similarly treated Tcf3tm1(TCF3/HLF)Homy heterozygotes
|
|
• pIpC-treated mice exhibit an increase in B cell precursors in the bone marrow compared with similarly treated Tcf3tm1(TCF3/HLF)Homy heterozygotes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice injected with poly(I)poly(C) exhibit normal B cell development
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 1 and 3 months after poly(I)-poly(C) injection, thymus size is reduced
|
|
• 1 month after poly(I)-poly(C) injection, the number of thymocytes is reduced and by 3 months the number of thymocytes is reduced to 1/8 that in control mice
|
|
• 1 and 3 months after poly(I)-poly(C) injection, in the thymus and bone marrow lymphocyte progenitors induce B cell development at the expense of T cell development; however myeloid and B cell lineage development in the bone marrow is normal
|
|
• after poly(I)-poly(C) injection, B cell development is impaired in the spleen but not in the bone marrow
|
|
• 1 and 3 months after poly(I)-poly(C) injection, a progressive increase in the number of double negative cells is seen in the thymus; however many of these cells are B cells
|
|
• 1 and 3 months after poly(I)-poly(C) injection, a progressive decrease in the number of double positive cells is seen in the thymus
|
|
• 1 and 3 months after poly(I)-poly(C) injection, T cell development is arrested at the CD44+CD25- pro-T cell or earlier stage
(J:99747)
• 3 weeks after induction of cre expression by poly(I):poly(C) treatment, mice manifest a block in T cell development in the thymus
(J:125869)
|
|
• 3 weeks after induction of cre expression by poly(I):poly(C) treatment, fraction of PDCs is elevated in the spleen
|
|
• 3 weeks after induction of cre expression by poly(I):poly(C) treatment, proportion of conventional Cd11chigh MHC class II+ dendritic cells is reduced 2.5 fold; decrease in the fraction of Cd11b+ dendritic cells corresponding to the CD8- subset is consistently observed
|
|
• one month after IFN-induced deletion, mutants show a gradual deletion of marginal zone B cells, from 10% to 3% of splenic B cells
(J:76240)
• after poly(I)-poly(C) injection, marginal zone B cells are drastically reduced in spleen
(J:99747)
|
|
• 1 and 3 months after poly(I)-poly(C) injection, a progressive increase in the number of B cells is seen in the thymus
(J:99747)
• after poly(I)-poly(C) injection, pro-B and pre-B cell numbers are increased in the thymus
(J:99747)
• 3 weeks after induction of cre expression by poly(I):poly(C) treatment, increased B cell development in the thymus is observed
(J:125869)
|
|
• after poly(I)-poly(C) injection, follicular B cells are slightly increased in spleen
|
|
• 1 and 3 months after poly(I)-poly(C) injection, a progressive decrease in the number of single positive cells is seen in the thymus
|
|
• 3 weeks after induction of cre expression by poly(I):poly(C) treatment, fraction of Cd11b+ Cd11c- monocytes/macrophages is elevated in the spleen
|
|
• 3 weeks after induction of cre expression by poly(I):poly(C) treatment, fraction of Cd11b+ Cd11c- monocytes/macrophages is elevated in the spleen
|
|
• 3 weeks after induction of cre expression by poly(I):poly(C) treatment, there is decreased splenic dendritic cell content
|
|
• 1 and 3 months after poly(I)-poly(C) injection, thymus size is reduced
|
|
• 1 month after poly(I)-poly(C) injection, the number of thymocytes is reduced and by 3 months the number of thymocytes is reduced to 1/8 that in control mice
|
|
• 1 and 3 months after poly(I)-poly(C) injection, in the thymus and bone marrow lymphocyte progenitors induce B cell development at the expense of T cell development; however myeloid and B cell lineage development in the bone marrow is normal
|
|
• after poly(I)-poly(C) injection, B cell development is impaired in the spleen but not in the bone marrow
|
|
• 1 and 3 months after poly(I)-poly(C) injection, a progressive increase in the number of double negative cells is seen in the thymus; however many of these cells are B cells
|
|
• 1 and 3 months after poly(I)-poly(C) injection, a progressive decrease in the number of double positive cells is seen in the thymus
|
|
• 1 and 3 months after poly(I)-poly(C) injection, T cell development is arrested at the CD44+CD25- pro-T cell or earlier stage
(J:99747)
• 3 weeks after induction of cre expression by poly(I):poly(C) treatment, mice manifest a block in T cell development in the thymus
(J:125869)
|
|
• 3 weeks after induction of cre expression by poly(I):poly(C) treatment, fraction of PDCs is elevated in the spleen
|
|
• 3 weeks after induction of cre expression by poly(I):poly(C) treatment, proportion of conventional Cd11chigh MHC class II+ dendritic cells is reduced 2.5 fold; decrease in the fraction of Cd11b+ dendritic cells corresponding to the CD8- subset is consistently observed
|
|
• one month after IFN-induced deletion, mutants show a gradual deletion of marginal zone B cells, from 10% to 3% of splenic B cells
(J:76240)
• after poly(I)-poly(C) injection, marginal zone B cells are drastically reduced in spleen
(J:99747)
|
|
• 1 and 3 months after poly(I)-poly(C) injection, a progressive increase in the number of B cells is seen in the thymus
(J:99747)
• after poly(I)-poly(C) injection, pro-B and pre-B cell numbers are increased in the thymus
(J:99747)
• 3 weeks after induction of cre expression by poly(I):poly(C) treatment, increased B cell development in the thymus is observed
(J:125869)
|
|
• after poly(I)-poly(C) injection, follicular B cells are slightly increased in spleen
|
|
• 1 and 3 months after poly(I)-poly(C) injection, a progressive decrease in the number of single positive cells is seen in the thymus
|
|
• 3 weeks after induction of cre expression by poly(I):poly(C) treatment, fraction of Cd11b+ Cd11c- monocytes/macrophages is elevated in the spleen
|
|
• 3 weeks after induction of cre expression by poly(I):poly(C) treatment, fraction of Cd11b+ Cd11c- monocytes/macrophages is elevated in the spleen
|
|
• 1 and 3 months after poly(I)-poly(C) injection, thymus size is reduced
|
|
• 1 month after poly(I)-poly(C) injection, the number of thymocytes is reduced and by 3 months the number of thymocytes is reduced to 1/8 that in control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mesenchymal stem cells (MSCs) from mutant mice show normal proliferative capacity and lineage commitment
• hematopoietic stem cells (HSCs) appear normal, and white blood cell (WBC), red blood cell (RBC) or platelet counts exhibit no deficiency
• bone marrow displays normal B-cell, monocyte, and granulocyte lineages at 12 and 35 days after recombination
|
| N |
• 2 months after removal of 75%, mutants were able to fully regenerate lost tissue, similar to wild-type
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at day 6, cellularity is low and decreases further until day 23
|
|
• there is 17-fold expansion of early pro-B cells, until day 23
|
|
• numbers of double positive thymocytes is reduced, while double positive numbers are increased relative to controls
|
|
• partial block at DN3 stage is observed
|
|
• upon induction of transgene, bone marrow contains ~9 times more B lmphocytes compared to control
|
|
• at day 6, cellularity is low and decreases further until day 23
|
|
• there is 17-fold expansion of early pro-B cells, until day 23
|
|
• numbers of double positive thymocytes is reduced, while double positive numbers are increased relative to controls
|
|
• partial block at DN3 stage is observed
|
|
• upon induction of transgene, bone marrow contains ~9 times more B lmphocytes compared to control
|
|
• at day 6, cellularity is low and decreases further until day 23
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• even in the absence of pI-pC injection to induce Cre expression some recombination is seen and all mice are dead before 4 weeks of age
|
|
• histiocytes containing the recombined allele are found in extranodal sites predominantly in the skin consistent with nonlymphoid leukemia of the histiocytic type
|
|
• seen in the spleen and liver
|
|
• red and white blood cell numbers in the bone marrow are reduced with red blood cells virtually absent
|
|
• increased proliferation and apoptosis are seen
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• macrophages more sensitive to Salmonella induced apoptosis
• kinetics of apoptosis faster
• specific to Salmonella infection
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following induction with IFN or pI-pC and 70% partial hepatectomy, abnormal architecture, hepatocyte death, and accumulation of cytoplasmic fat droplets were observed in the regenerating liver
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in cultured hepatocytes treated with poly(I)poly(C) 80% of anaphase cells have sister chromatids that fail to properly disjoin so that mitosis produces cells with micronuclei and abnormally large nuclei
|
|
• after a injection with 400 ul poly(I)poly(C) and a two thirds hepatectomy, liver regeneration occurs but cells are larger, contain larger nuclei, and increased DNA content (many cell with 8C, 16C,or 32C DNA content) suggesting that regeneration occurs by genome replication without cell proliferation
|
|
• 3 days after a injection with 400 ul poly(I)poly(C) severe bone marrow aplasia is seen with only erythrocytes present; however, by 31 days after injection bone marrow cell numbers return to normal (all of these new hematopoeitic cells contain unrecombined alleles)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• within 6 months of induction, lumen-filling renal tubule neoplasias are observed unlike in control mice
• tumors often block urinary flow
|
|
• within 6 months of induction, lumen-filling renal tubule neoplasias are observed unlike in control mice
• tumors often block urinary flow
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• most die during the second week after the first pI/C injection to induce cre-mediated deletion of Anapc2 in the liver and lymphocytes
|
|
• hepatocytes of mutants treated with pI/C lack glycogen
|
|
• hepatocytes are greatly enlarged, lack nuclear membranes, and contain condensed chromosomes in 6 of 10 mutants after pI/C injection
• 72% of mitotic hepatocytes are in a prometaphase-like state with condensed chromatin
|
|
• levels of the liver enzymes alanine aminotransferase and glutamate dehydrogenase are highly elevated in pI/C injected mutants, indicating functional impairment and damage of hepatocytes
|
|
• quiescent hepatocytes of some but not all livers enter into a proliferative state, resulting in a mitotic arrest
• 2/3 hepatectomy in mutants transplanted with wild-type bone marrow and treated with pI/C caused 70% of hepatoctyes to re-enter the cell cycle and embark on proliferation and arrest in metaphase 3 to 5 days after hepatectomy
|
|
• die from acute liver failure after pI/C injection
|
|
• the 4 of 10 mutants injected with pI/C with normal livers and 2 of 6 with abnormal livers show severe anemia
|
|
• the 4 of 10 mutants injected with pI/C with normal livers show decreased hemoglobin levels
|
|
• levels of bilirubin are highly elevated in pI/C injected mutants
|
|
• levels of the liver enzymes alanine aminotransferase and glutamate dehydrogenase are highly elevated in pI/C injected mutants, indicating functional impairment and damage of hepatocytes
|
|
• hepatocytes of mutants treated with pI/C lack glycogen
|
|
• develop severe bone marrow aplasia within 4 days of pI/C injection; by day 4, majority of nucleated cells disappear from the bone marrow which contains mainly erythrocytes and a few lymphocytes
|
|
• quiescent hepatocytes of some but not all livers enter into a proliferative state, resulting in a mitotic arrest
• 2/3 hepatectomy in mutants transplanted with wild-type bone marrow and treated with pI/C caused 70% of hepatoctyes to re-enter the cell cycle and embark on proliferation and arrest in metaphase 3 to 5 days after hepatectomy
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 2-3 weeks after induction of cre expression with pI-pC, number of HSCs in bone marrow is decreased with loss of CMPs, GMPs and mature myeloid cells while MEPs are increased; mature granulocytes have disappeared
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• TNF levels in the serum of mice expressing Cre are lower by more than half compared to controls 3 hours after LPS injection
|
|
• two weeks after induction of Cre recombinase, mice are more resistant to endotoxin shock than in controls
• 6 of 8 mice survive endotoxin induction with LPS and D-galactosamine while 7 of 8 controls die within 16 hours of injection
|
|
• TNF levels in the serum of mice expressing Cre are lower by more than half compared to controls 3 hours after LPS injection
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• the distinction between medulla and cortex is lost in a third of the mice examined after Cre induction
• the medulla becomes populated with immature lymphoblasts
|
|
• thymus weight is reduced to a mean of 42.0 mg before Cre induction compared to 73.9 mg in control mice
|
|
• starting at 7 weeks post-Cre induction, there is a significant increase in spleen with a mean increase of about 40%
|
|
• increased number of myeloid progenitors are found in the bone marrow 5 weeks after Cre-induction (34.5% vs 23.9% in controls)
|
|
• there are increased number of myeloid progenitor cells found in the spleen but normal number of neutrophils and granulocytes in circulation
|
|
• small megakaryocytes are found in the bone marrow after Cre induction
|
|
• decreased megakarycote numbers are found in the bone marrow
|
|
• Howell-Jolly bodies are present in peripheral blood smears
• more than 2 months after Cre induction, 0.51% of erythrocytes contain Howell-Jolly bodies compared of 0.16% of control mice
|
|
• one week after Cre recombinase induction, the number of platelets in the blood is decreased by almost half
• this low number persists for at least five weeks after Cre expression
|
|
• there is an increased fraction of HSC (11.7%) found in bone marrow 5 weeks after Cre recombinase induction compared to the 6.4% found in control mice
|
|
• increased number of mast cells are found in the red pulp of the spleen
|
|
• immature neutrophils make up 18.4% of splenocytes compared to 3.9% in controls
|
|
• starting three weeks after induction of Cre recombinase, there is a significant drop in lymphocyte numbers
|
|
• less mature B cells (15.1% of splenocytes) are found in the spleen compared to wild-type (23.6%)
|
|
• less T cells are found in the spleen than in controls
|
|
• there is a large decrease in the percentage of double-positive T cells found in the thymus after Cre induction (from 76.7% to 0.8%)
|
|
• CD4 T cells in the thymus are reduced more than 4-fold
|
|
• CD8 T cells are reduced by 2-fold in the thymus
|
|
• immature monocytes make up 9.8% of splenocytes compared to 1.8% in controls
|
|
• there is a striking expansion of the red bulb seven weeks after Cre-induction
|
|
• there is a reduction and disbursement of the white pulp matter
|
|
• one mouse had lymphoma of a cervical lymph node of the brain
|
|
• a metastatic thymic lymphoma was found in the liver of one mouse
|
|
• there are increased number of myeloid progenitor cells found in the spleen but normal number of neutrophils and granulocytes in circulation
|
|
• increased number of mast cells are found in the red pulp of the spleen
|
|
• immature neutrophils make up 18.4% of splenocytes compared to 3.9% in controls
|
|
• starting three weeks after induction of Cre recombinase, there is a significant drop in lymphocyte numbers
|
|
• less mature B cells (15.1% of splenocytes) are found in the spleen compared to wild-type (23.6%)
|
|
• less T cells are found in the spleen than in controls
|
|
• there is a large decrease in the percentage of double-positive T cells found in the thymus after Cre induction (from 76.7% to 0.8%)
|
|
• CD4 T cells in the thymus are reduced more than 4-fold
|
|
• CD8 T cells are reduced by 2-fold in the thymus
|
|
• immature monocytes make up 9.8% of splenocytes compared to 1.8% in controls
|
|
• the distinction between medulla and cortex is lost in a third of the mice examined after Cre induction
• the medulla becomes populated with immature lymphoblasts
|
|
• thymus weight is reduced to a mean of 42.0 mg before Cre induction compared to 73.9 mg in control mice
|
|
• starting at 7 weeks post-Cre induction, there is a significant increase in spleen with a mean increase of about 40%
|
|
• there is a striking expansion of the red bulb seven weeks after Cre-induction
|
|
• there is a reduction and disbursement of the white pulp matter
|
|
• Peyer's patches of mice after Cre induction are smaller than in controls
|
|
• lymph nodes of mice after Cre induction are smaller than in controls
|
|
• the distinction between medulla and cortex is lost in a third of the mice examined after Cre induction
• the medulla becomes populated with immature lymphoblasts
|
|
• thymus weight is reduced to a mean of 42.0 mg before Cre induction compared to 73.9 mg in control mice
|
|
• a metastatic thymic lymphoma was found in the liver of one mouse
|
|
• starting at 7 weeks post-Cre induction, there is a significant increase in spleen with a mean increase of about 40%
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• induction of Cre by pI-pC administration leads to death within 10 days with a median survival time of 6 days after first injection of pI-pC
• lethally irradiated wild-type mice that receive mutant bone marrow die within 11 days of Cre induction in the bone marrow derived cells
|
|
• there is a profound reduction in the ability of CD4 and CD8 T cells to proliferate in response to mitogenic stimuli 6 days after induction of Cre by pI-pC administration
|
|
• there is almost a complete absence of nucleated cells in the bone marrow including stem and progenitor cells 6 days after induction of Cre by pI-pC administration
|
|
• there is almost a complete absence of granulocytes in the bone marrow 6 days after induction of Cre by pI-pC administration
|
|
• mean RBC counts are reduced by more than half 6 days after induction of Cre by pI-pC administration
|
|
• percentage of hematocrit is reduced by more than half 6 days after induction of Cre by pI-pC administration
|
|
• hemoglobulin content is reduced by more than half 6 days after induction of Cre by pI-pC administration
|
|
• there is almost a complete absence of granulocytes in the bone marrow 6 days after induction of Cre by pI-pC administration
|
|
• there is almost a complete absence of B-cells in the bone marrow 6 days after induction of Cre by pI-pC administration
|
|
• there is almost a complete absence of hematopoietic progenitors in the bone marrow 6 days after induction of Cre by pI-pC administration
|
|
• there is a profound reduction in the ability of CD4 and CD8 T cells to proliferate in response to mitogenic stimuli 6 days after induction of Cre by pI-pC administration
|
|
• there is almost a complete absence of granulocytes in the bone marrow 6 days after induction of Cre by pI-pC administration
|
|
• there is almost a complete absence of B-cells in the bone marrow 6 days after induction of Cre by pI-pC administration
|
|
• there is a profound reduction in the ability of CD4 and CD8 T cells to proliferate in response to mitogenic stimuli 6 days after induction of Cre by pI-pC administration
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• reduced survival (50% versus 70% WT littermate controls) after two thirds partial hepatectomy
|
|
• in mice treated with poly I/C (to drive Cre expression), there is a reduction in number of proliferating hepatocytes 36 to 48 hours after two-thirds partial hepatectomy (PH)
• 7 days after PH, the liver-to-body weight ratio is lower compared to control mice
• 15 days after PH, there are no significant differences in the liver-to-bodyweight ratio indicating that after the initial delay mutant livers can complete regeneration
|
|
• higher levels in the serum are observed 24 hours after PH
|
|
• higher levels in the serum are observed 24 hours after PH
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
 |
• 30% reduction in the number of NK cells found in the spleen 5 days after Cre induction
• 90% of the remaining NK cells still expressed IL2rg indicating they did not express Cre upon induction
|
|
|
• 30% reduction in the number of NK cells found in the spleen 5 days after Cre induction
• 90% of the remaining NK cells still expressed IL2rg indicating they did not express Cre upon induction
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• platelets from chimeric mice containing bone marrow with the conditional knockout express 15% less alphaIIbeta3 integrin on their surface
|
|
• platelets fail to form lamellipodia and spread out on a fibrinogen coated surface when exposed to low levels of thrombin
|
|
• conditional knockout platelets fail to aggregate in vitro to high concentrations of thrombin, ADP, collagen, and other platelet agonists
• platelets fail to attach to a collagen coated surface even under low shear stress compared to control platelets that cover 53% of the surface area
• platelets fail to bind fibrinogen as measured by flow cytometry
• degranulation of mutant platelets to low levels of agonist is half that of chimeric controls
• Mn2+ addition enables platelets to bind fibrinogen
|
|
• conditional knockout platelets fail to aggregate in vitro to high concentrations of thrombin, ADP, collagen, and other platelet agonists
• platelets fail to attach to a collagen coated surface even under low shear stress compared to control platelets that cover 53% of the surface area
• platelets fail to bind fibrinogen as measured by flow cytometry
• degranulation of mutant platelets to low levels of agonist is half that of chimeric controls
• Mn2+ addition enables platelets to bind fibrinogen
|
|
• thrombus formation of injured mesenteric arterioles does not occur in mice containing bone marrow with the conditional knockout
|
|
• all chimeric mice containing bone marrow with the conditional knockout bleed longer than 15 minutes compared to control chimeras that on average stop bleeding at 7.3 minutes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• within 6 months, pIpC-treated mice die of leukemia
|
|
• pIpC-treated mice develop acute B-lineage leukemia by 6 months of age unlike control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 4-6 days after induction of cre expression with pI:pC (poly(I:C)), mice become moribund and die
|
|
• 4 days after pI:pC administration, apoptotic hepatocytes are observed around the central vein; extended sinoids and apoptotic figures are seen
• on day 6, apoptotic figures and ubiquitous degeneration of hepatocytes over all zones of hepatic lobules are observed
|
|
• on day 7 after treatment, lytic necrosis is observed over all hepatic lobules
|
|
• 4 days after treatment, immature hepatocytes around the portal field display swelling and are vacuolized
|
|
• upon induction of cre expression with pI:pC treatment, mice develop severe jaundice
|
|
• treated mice show severe liver injury within 4-6 days of pI:pC treatment manifested by high levels of hepatocyte apoptosis and tissue necrosis
|
|
• after cre induction, treated mice exhibit hyperbilirubinemia
|
|
• 4 days after pI:pC administration, apoptotic hepatocytes are observed around the central vein; extended sinoids and apoptotic figures are seen
• on day 6, apoptotic figures and ubiquitous degeneration of hepatocytes over all zones of hepatic lobules are observed
|
|
• on day 7 after treatment, lytic necrosis is observed over all hepatic lobules
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following pIpC injection the density of crystal inclusions in the proximal tubules is decreased but not eliminated
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• following pIpC injection crystal inclusions are no longer detectable in the proximal tubules
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• despite cellular defects in T cell proliferation, activated T cells exposed to pIpC blast normally
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following treatment with a retroviral cre, mouse embryonic fibroblasts fail to proliferate in culture unlike wild-type cells
|
| N |
• despite cellular defects in T cell proliferation, activated T cells blast normally
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice withdrawn from tetracycline and treated with polyinosine-polycyticylic acid (pIpC) show a decrease in survival with median survival of 116.5 days
|
|
• majority of pIpC treated mice (85%) develop an exclusively myeloid and primary acute leukemia phenotype
• 5% of mice remain in the chronic phase of the disease
• about 10% of mice develop an accelerated phase-like phenotype but with less than 20% blasts
• however, mice do not develop lymphoid leukemias
|
|
• in pIpC treated mice
|
|
• hemoglobin levels are decreased in pIpC treated mice
|
|
• upon withdrawal of tetracycline and treatment with pIpC, mice develop moderate, but persistent (2-3 fold) increase of white blood counts
• white blood cell counts at the terminal endpoint are elevated, indicating a dramatic preterminal proliferative change in kinetics of their disease
|
|
• upon withdrawal of tetracycline and treatment with pIpC, mice show marked expansion of the granulocyte compartment
• increase in infiltration of tissues with both granulocytes and immature cells
|
|
• disease progression in in pIpC treated mice is frequently accompanied by an increase in basophils
|
|
• the myeloid progenitor compartment is expanded in pIpC treated mice, including the granulocyte monocyte progenitor compartment
|
|
• expansion of the lineage-negative (Lin-) bone marrow fraction in pIpC treated mice
• however, no differences are seen in total Lin-Sca+c-kit+ (LSK) numbers, long-term and short-term hematopoietic stem cell or multipotent progenitor proportions
|
|
• hematopoietic stem cells show an increased ability to serially replate compared to control cells
|
|
• in pIpC treated mice
|
|
• upon withdrawal of tetracycline and treatment with pIpC, mice develop moderate, but persistent (2-3 fold) increase of white blood counts
• white blood cell counts at the terminal endpoint are elevated, indicating a dramatic preterminal proliferative change in kinetics of their disease
|
|
• upon withdrawal of tetracycline and treatment with pIpC, mice show marked expansion of the granulocyte compartment
• increase in infiltration of tissues with both granulocytes and immature cells
|
|
• disease progression in in pIpC treated mice is frequently accompanied by an increase in basophils
|
|
• in pIpC treated mice
|
|
• in pIpC treated mice
|
|
• in pIpC treated mice
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| chronic myeloid leukemia | DOID:8552 |
OMIM:608232 |
J:227558 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice withdrawn from tetracycline and treated with polyinosine-polycyticylic acid (pIpC) show a median survival of 125.5 days
|
|
• 26% of mice treated with pIpC develop lymphoid acute leukemias
• 70% of mice treated with pIpC develop myeloid acute leukemias
• increase in infiltration of tissues with immature cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pI-pC treated mutants are growth retarded
|
|
• pI-pC treated mutants exhibit numerous abnormal macrophages that contain DNA in lysosomes in the bone marrow, spleen and other tissues
|
|
• affected joints of pI-pC treated mutants show 5-100 fold elevation of TNF-alpha, IL-1beta, IL-6, IL-10, IFN-beta, and IFN-gamma mRNA levels, the set of cytokines that are elevated in joints of humans with rheumatoid arthritis
|
|
• serum pI-pC treated mutants shows elevated levels of IL-18 protein
|
|
• serum of pI-pC treated mutants shows elevated levels of TNF-alpha before joints show abnormalities
|
|
• joints of pI-pC treated mutants show severe synovitis with villus proliferation accompanied by pannus formation; pannus fills the joint cavity, erodes cartilage, destroys bones, and occasionally penetrates the bone marrow
• exhibit infiltration of subsynovial tissues by T cells and neutrophils
|
|
• poly(I)-poly(C) (pI-pC) treated mutants develop polyarthritis in a time-dependent manner; forelimbs and hindlimbs begin to swell 2-3 months after pI-pC treatment
• swelling first affects the digits, then the foot, and finally the wrists and ankles
|
|
• pI-pC treated mutants exhibit numerous abnormal macrophages that contain DNA in lysosomes in the bone marrow, spleen and other tissues
|
|
• pI-pC treated mutants carry a low but significant level of DNA in serum
|
|
• affected joints of pI-pC treated mutants show 5-100 fold elevation of TNF-alpha, IL-1beta, IL-6, IL-10, IFN-beta, and IFN-gamma mRNA levels, the set of cytokines that are elevated in joints of humans with rheumatoid arthritis
|
|
• serum pI-pC treated mutants shows elevated levels of IL-18 protein
|
|
• serum of pI-pC treated mutants shows elevated levels of TNF-alpha before joints show abnormalities
|
|
• joints of pI-pC treated mutants show severe synovitis with villus proliferation accompanied by pannus formation; pannus fills the joint cavity, erodes cartilage, destroys bones, and occasionally penetrates the bone marrow
• exhibit infiltration of subsynovial tissues by T cells and neutrophils
|
|
• poly(I)-poly(C) (pI-pC) treated mutants develop polyarthritis in a time-dependent manner; forelimbs and hindlimbs begin to swell 2-3 months after pI-pC treatment
• swelling first affects the digits, then the foot, and finally the wrists and ankles
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| rheumatoid arthritis | DOID:7148 |
OMIM:180300 |
J:114982 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• of all pIpC-treated mice
|
|
• all pIpC-treated mice die of myeloproliferative disorder accompanied by an expansion of myeloid cells in the bone marrow, an infiltration of myeloid cells in the spleen, and the appearance of blast cells in the blood faster
|
|
• all pIpC-treated mice die of myeloproliferative disorder accompanied by an expansion of myeloid cells in the bone marrow, an infiltration of myeloid cells in the spleen, and the appearance of blast cells in the blood faster
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• of all pIpC-treated mice faster than control mice
|
|
• all pIpC-treated mice die of myeloproliferative disorder accompanied by an expansion of myeloid cells in the bone marrow, an infiltration of myeloid cells in the spleen, and the appearance of blast cells in the blood faster than control mice
|
|
• all pIpC-treated mice die of myeloproliferative disorder accompanied by an expansion of myeloid cells in the bone marrow, an infiltration of myeloid cells in the spleen, and the appearance of blast cells in the blood faster than control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• of all pIpC-treated mice faster than control mice
|
|
• all pIpC-treated mice die of myeloproliferative disorder accompanied by an expansion of myeloid cells in the bone marrow, an infiltration of myeloid cells in the spleen, and the appearance of blast cells in the blood faster than control mice
|
|
• all pIpC-treated mice die of myeloproliferative disorder accompanied by an expansion of myeloid cells in the bone marrow, an infiltration of myeloid cells in the spleen, and the appearance of blast cells in the blood faster than control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following treatment with pIpC, the number of progenitors, enriched hematopoietic stem cells, and pure hematopoietic stem cells are increased compared to similarly treated wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• all mice die within 8 days of treatment with pIpC unlike control mice
|
|
• following pIpC treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 90% mortality between 1 and 3 weeks after injection with polyI/polyC
• remaining mice die over the next 4 weeks
|
|
• deficiency of hematopoietic cells in the bone marrow
|
|
• mice are ill and profoundly pancytopenic by weeks 1-2 after polyI/polyC injection
• some mice develop mild or transient pancytopenia but still experience sudden death
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice normal for about 4 weeks after polyI/polyC injection
• begin to develop cancers after 4 weeks
• 100% develop tumors with a median onset of 11 weeks after polyI/polyC injection
• sometimes an increase in circulating tumor cells
|
|
• 3 out of 23 mice with rhabdoid tumors
|
|
• periportal lymphoma in the liver
|
|
• 20 of 23 mice have CD8+ T cell lymphomas
• tumor cell types suggestive of malignant lymphocytes
|
|
• increase in circulating eosinophiles
|
|
• effacement of normal architecture
|
|
• sometimes dramatically
|
|
• effacement of the normal architecture of involved lymph nodes
|
|
• often a mild and progressive decrease in blood cell counts
|
|
• increase in circulating eosinophiles
|
|
• effacement of normal architecture
|
|
• sometimes dramatically
|
|
• periportal lymphomas
|
|
• sometimes dramatically
|
|
• in liver and spleen 18-24 hours after polyI/polyC injection
|
|
• 20 of 23 mice have CD8+ T cell lymphomas
• tumor cell types suggestive of malignant lymphocytes
|
|
• sometimes dramatically
|
|
• sometimes dramatically
|
|
• 3 out of 23 mice with rhabdoid tumors
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• development of hemangiomas leads to premature death starting at ~55 weeks of age with induced cre expression
|
|
• mice show widespread development of hemangiomas after cre induction; lesions are most exaggerated in uterus, visible at 6-8 weeks
|
|
• discrete liver hemangiomas and occasionally angiosarcomas are observed in aged mice (7/10 that died at 50-82 weeks and 2/2 examined at 90-102 weeks)
|
|
• in ~9% of mice, lesions progress to lethal angiosarcomas
|
|
• all mice display mild vascular abnormalities with cre expression
|
|
• discrete liver hemangiomas and occasionally angiosarcomas are observed in aged mice (7/10 that died at 50-82 weeks and 2/2 examined at 90-102 weeks)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• following pIpC-induction, dendritic cells transplanted into the footpad exhibit normal drainage into lymph nodes
|
|
• abolished in pIpC-induced mice
|
|
• following pIpC-induction, dendritic cells fail to adhere to and migrate on a 2-D substrate unlike wild-type dendritic cells
• however, dendritic cells from pIpC-induced mice exhibit normal migration in 3D matrix
|
|
• abolished in pIpC-induced mice
|
|
• abolished in pIpC-induced mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• when cells from a mouse treated with pIpC at 6 to 12 weeks where exposed to IL-7 in a clonogenic assay, the number and size of pre-B cell colonies is reduced compared to in wild-type mice
|
|
• following treatment with pIpC at 6 to 12 weeks, the progenitor compartment is enlarged and the number of hematopoietic stem cells is increased compared to in wild-type mice
|
|
• when cells from a mouse treated with pIpC at 6 to 12 weeks where exposed to IL-7 in a clonogenic assay, the number of myeloid colony forming units is increased 2-fold, all types of myeloid-derives cells are present at a 6-fold higher level, and granulo-mono-erythromegakaryocitic colonies are denser and contain a 5-fold increase in primitive common myeloid progenitors relative to in wild-type mice
|
|
• following treatment with pIpC at 6 to 12 weeks, the total number of bone marrow cells is nearly one third less than in wild-type mice
|
|
• following treatment with pIpC at 6 to 12 weeks, mice exhibit decreased erythrocyte numbers compared to in wild-type mice
|
|
• following treatment with pIpC at 6 to 12 weeks, some mice are thrombocytotic
|
|
• following treatment with pIpC at 6 to 12 weeks, the number of lymphoid B cells is slightly decreased compared to in wild-type mice
|
|
• following treatment with pIpC at 6 to 12 weeks, mice exhibit decreased splenocyte numbers compared to in wild-type mice
|
|
• when cells from a mouse treated with pIpC at 6 to 12 weeks where exposed to IL-7 in a clonogenic assay, the number and size of pre-B cell colonies is reduced compared to in wild-type mice
|
|
• following treatment with pIpC at 6 to 12 weeks, the number of lymphoid B cells is slightly decreased compared to in wild-type mice
|
|
• following treatment with pIpC at 6 to 12 weeks, mice exhibit decreased splenocyte numbers compared to in wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 5 months post-transplant of wild-type bone marrow into deficient mice 1.5 months after Gba-depletion results in significantly higher glucosylceramidase activity in bone marrow, spleen and liver of recipients
|
|
• after 16 months of disease (cre) induction, significantly reduced compared to control
|
|
• after 16 months of disease (cre) induction, significantly reduced compared to control
|
|
• after 16 months of disease (cre) induction, significantly reduced compared to control
|
|
• after disease (cre) induction following birth, 12 month -old Gba-deficient mice have disrupted splenic architecture
|
|
• demarcation of red and white pulp is not evident
|
|
• spleen, thymus, liver and lymph nodes of 12 month old cre-induced Gba-null mice show massive infiltration of mainly multinucleated Gaucher cells, and cytoplasm had "wrinkled tissue-paper"-like appearance
|
|
• after disease (cre) induction following birth, 12 month -old Gba-deficient mice have disrupted splenic architecture
|
|
• demarcation of red and white pulp is not evident
|
|
• 5 months after bone marrow transplant, no Gaucher cells are observed
• if Gaucher disease is allowed to progress for 7.5 months before bone marrow transplant, when examined at 13 months of age, recipients have been cleared of all (4/6) or all but a few (2/6) Gaucher cells
|
|
• after 16 months of disease (cre) induction, liver is slightly enlarged, but less so than spleen
|
|
• after 16 months of disease (cre) induction, liver is pale
|
|
• bone marrow shows massive infiltration by Gaucher cells
|
|
• after 16 months of disease (cre) induction, liver is slightly enlarged, but less so than spleen
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Gaucher's disease type I | DOID:0110957 |
OMIM:230800 |
J:113751 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• numbers drastically reduced 15 days after the first pIpC injection to induce cre expression
• numbers restored by 40 days
• Gfi1b excision is incomplete
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• pIpC injection induces cre expression
|
|
• in the peripheral blood
|
|
• in peripheral blood
|
|
• increased frequency of hematopoietic stem cells in bone marrow, spleen, and peripheral blood
|
|
• due to the expansion of erythroid progenitors
|
|
• increased apoptosis but still below 2.5%
• increased levels of reactive oxygen species
|
|
• due to the expansion of erythroid progenitors
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die shortly after birth, even in the absence of cre induction by poly(I:C) administration
|
|
• E14.5 fetal liver cells transplanted into wild-type hosts engraft normally but fail to replenish blood leukocytes after cre induction
• two weeks after cre induction, the contribution of the mutant cells to blood leukocytes is diminished by a fourth
• the contribution of these fetal liver cells to peripheral blood cells including myeloid, B-lymphoid and T-lymphoid lineages is negligible after 23 weeks of cre induction
• very few donor derived hematopoetic stem cells are found in the bone marrow after 23 weeks of cre induction
|
|
• E14.5 embryos have slightly lower total liver cellularity even in the absence of cre induction by poly(I:C) administration
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Loss of bone marrow hematopoietic cells in Ep400tm3Fuku/Ep400tm3.1Fuku Tg(Mx1-cre)1Cgn/0 mice
|
• pIpC-treated mice die within 14 days unlike similarly treated heterozygous mice
|
|
• pIpC-treated mice exhibit a reduction in nucleated hematopoietic cells and an increase in CD71-Ter119high in the bone marrow cavity compared with similarly treated heterozygous mice
|
|
• bone marrow cells from pIpC-treated mice exhibit reduced colony formation in response to IFN-beta treatment unlike similarly treated cells from heterozygous mice
• however, colony formation in the absence of IFN-beta is normal
|
|
• pIpC-treated mice exhibit a reduction of nucleated cells, B220 B+ cells, and Ter119+ erythroid cells in the bone marrow compared with similarly treated heterozygous mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit a reduction in Mac1+Gr-1mid-lo monocyte/macrophage lineage and Mac-1+Gr-1hi granulocyte lineage compared with similarly treated heterozygous mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit an increase in apoptosis compared to in similarly treated heterozygous mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• hematopoietic stem and progenitor cells are more sensitive to lenalidomide in culture than cells from Csnk1a1tm1.1Ybn/+ Tg(Mx1-cre)1Cgn mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in response to transient focal cerebral ischemia, homozygotes exhibit a significantly increased number of apoptotic neuronal and non-neuronal cells in infarcted areas
• however, no significant differences are observed in cell proliferation, monocyte/macrophage infiltration, neovascularization or initial gliosis
|
|
• homozygotes display increased susceptibility to ischemia/reperfusion cerebral injury relative to wild-type mice, despite a normal brain vasculature
|
|
• in response to transient focal cerebral ischemia, 2-3-mo-old homozygotes exhibit a 35% increase in brain infarct size relative to wild-type mice
|
| N |
• homozygotes are viable, fertile and anatomically normal with no spontaneous bleeding, normal skin-wound healing, and normal hemostatic parameters, as shown by normal bleeding times and activated partial thromboplastin times, and in vitro plasma clotting activity, platelet aggregation and clot retraction
|
|
• in response to FeCl3-induced arterial injury, mutants exhibit a delay of several minutes in platelet thrombus formation, despite normal initial platelet vessel wall adhesion
• resulting arterial thrombi are well anchored to the vessel wall but grow slowly with continuous shedding of platelets or small platelet clumps
• platelet/platelet cohesion is reduced and occlusion of injured arterioles is significantly delayed, with most vessels remaining patent at the end of a 40-min observation period
|
|
• homozygotes display increased susceptibility to ischemia/reperfusion cerebral injury relative to wild-type mice, despite a normal brain vasculature
|
|
• in response to transient focal cerebral ischemia, 2-3-mo-old homozygotes exhibit a 35% increase in brain infarct size relative to wild-type mice
|
|
• in response to transient focal cerebral ischemia, homozygotes exhibit a significantly increased number of apoptotic neuronal and non-neuronal cells in infarcted areas
• however, no significant differences are observed in cell proliferation, monocyte/macrophage infiltration, neovascularization or initial gliosis
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• after induction with polyI:polyC, death 8 - 10 weeks after
|
|
• after induction with polyI:polyC, unsteady
|
|
• after induction with polyI:polyC
|
|
• after induction with polyI:polyC
|
|
• after induction with polyI:polyC
|
|
• after induction with polyI:polyC, dramatic
|
|
• after induction with polyI:polyC
|
|
• after induction with polyI:polyC
|
|
• after induction with polyI:polyC
|
|
• after induction with polyI:polyC
|
|
• after induction with polyI:polyC
|
|
• after induction with polyI:polyC
|
|
• after induction with polyI:polyC
|
|
• after induction with polyI:polyC
|
|
• after induction with polyI:polyC
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 20-fold increase in pIpC-treated mice
|
|
• expanded long term hematopoietic stem-like cells in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 50% of pIpC treated mice die by 7.5 months of age
|
|
• pIpC injected mice at 3 to 5 days of age develop overt signs of myeloproliferative disease beginning between 5 and 6 months of age
• pIpC injected mice show a shift in hematopoiesis from the marrow to the spleen
|
|
• myeloid progenitors from pIpC injected mice show increased proliferation
|
|
• spleen from pIpC injected mice shows a massive increase in myelopoiesis
|
|
• apoptosis is reduced in the bone marrow of pIpC injected mice
• bone marrow from pIpC injected mice is highly cellular, comprised of myeloid cells at various stages of differentiation
• increase in numbers of immature monocytic cells in the bone marrow of pIpC treated mice
• bone marrow from pIpC injected mice contains elevated numbers of CFU-GM and an increase in the numbers of CFU-GM that are hypersensitive to granulocyte-macrophage colony stimulating factor (GM-CSF) and CFU-GM colonies are larger than normal and show abnormal spreading morphology
|
|
• pIpC injected mice at 3 to 5 days of age exhibit elevated numbers of differentiated lymphoid cells by 3 months of age
|
|
• pIpC injected mice at 3 to 5 days of age exhibit elevated leukocyte counts by 3 months of age
• cultures from pIpC injected mice show an increase in the percentage of monocyte-macrophage cells
|
|
• pIpC injected mice show an increase in numbers of differentiated granulocytic cells
|
|
• pIpC injected mice at 3 to 5 days of age exhibit increased numbers of morphologically normal neutrophils by 3 months of age
|
|
• pIpC injected mice at 3 to 5 days of age exhibit increased numbers of morphologically normal lymphocytes by 3 months of age
|
|
• pIpC injected mice at 3 to 5 days of age exhibit increased numbers of morphologically normal monocytes by 3 months of age
• pIpC injected mice show an increase in numbers of immature monocytic cells in the bone marrow
|
|
• pIpC injected mice at 3 to 5 days of age exhibit elevated numbers of differentiated myeloid cells by 3 months of age
|
|
• spleens from pIpC injected mice contain large numbers of CFU-GM
|
|
• pIpC injected mice at 3 to 5 days of age exhibit progressive splenomegaly with extensive infiltration of myeloid cells at various stages of maturation
|
|
• pIpC injected mice at 3 to 5 days of age exhibit abnormal gait by 5-6 months of age
|
|
• pIpC injected mice at 3 to 5 days of age exhibit hunching by 5-6 months of age
|
|
• spleen from pIpC injected mice shows a massive increase in myelopoiesis
|
|
• pIpC injected mice at 3 to 5 days of age exhibit elevated leukocyte counts by 3 months of age
• cultures from pIpC injected mice show an increase in the percentage of monocyte-macrophage cells
|
|
• pIpC injected mice at 3 to 5 days of age exhibit increased numbers of morphologically normal lymphocytes by 3 months of age
|
|
• pIpC injected mice at 3 to 5 days of age exhibit elevated numbers of differentiated myeloid cells by 3 months of age
|
|
• pIpC injected mice show an increase in numbers of differentiated granulocytic cells
|
|
• pIpC injected mice at 3 to 5 days of age exhibit increased numbers of morphologically normal neutrophils by 3 months of age
|
|
• pIpC injected mice at 3 to 5 days of age exhibit increased numbers of morphologically normal monocytes by 3 months of age
• pIpC injected mice show an increase in numbers of immature monocytic cells in the bone marrow
|
|
• spleens from pIpC injected mice contain large numbers of CFU-GM
|
|
• pIpC injected mice at 3 to 5 days of age exhibit progressive splenomegaly with extensive infiltration of myeloid cells at various stages of maturation
|
|
• pIpC injected mice at 3 to 5 days of age have a disheveled appearance by 5-6 months of age
|
|
• pIpC injected mice at 3 to 5 days of age exhibit progressive splenomegaly with extensive infiltration of myeloid cells at various stages of maturation
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| juvenile myelomonocytic leukemia | DOID:0050458 |
OMIM:607785 |
J:90973 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• while platelets exhibit activation at high shear stress, they form looser aggregates and disintegrate more frequently than wild-type platelets
• platelet aggregates display reduced annexinV positivity after perfusion unlike wild-type platelets
• platelet calcium response fluctuates and is lower than in wild-type platelets
|
|
• while platelets exhibit activation at high shear stress, they form looser aggregates and disintegrate more frequently than wild-type platelets
• platelet aggregates display reduced annexinV positivity after perfusion unlike wild-type platelets
• platelet calcium response fluctuates and is lower than in wild-type platelets
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• unlike mice that do not carry Casp8tm1.1Yuan, compound heterozygous mutants survive injection with an anti-Fas Ab
|
|
• 2 days after induction of cre expression the ability of progenitor cells to form myeloid or B lymphoid colonies in culture or in transplant studies is significantly decreased
• the ability of these progenitors to differentiate into macrophages is also decreased after induction of cre expression
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following induction with pIpC, CFU-GMs (colony forming units Granulocyte-Macrophage, myeloid) are increased and CFU-IL-7 (early B-lineage committed, lymphoid) are decreased compared to in control mice
|
|
• following induction with pIpC, CFU-GEMMs (colony forming units Granulocyte, Erythroid, Macrophage, Megakaryocyte) are increased compared to in control mice
|
|
• in repopulation assays, bone marrow cells from pIpC treated lead to reduced donor-derived lymphocyte numbers compared to when untreated cells are used
|
|
• following pIpC treatment, myeloid progenitors are increased compared to in untreated mice
|
|
• following pIpC treatment, common lymphoid progenitors and lymphoid-primed multipotential progenitor are decreased compared to in untreated mice
|
|
• following induction with pIpC, BFU-Es (Burst-forming erythroid; early erythroid-committed, myeloid) are decreased compared to in controls
|
|
• mild to moderate following pIpC treatment
|
|
• mild to moderate following pIpC treatment
|
|
• mild to moderate following pIpC treatment
|
|
• B cells are gradually lost following pIpC treatment
|
|
• following pIpC treatment, the long term repopulating hematopoietic stem cells are increased 10-fold compared to in untreated mice
• in repopulation assays, bone marrow cells from pIpC treated lead to a 10-fold increase in long term repopulation hematopoietic stem cells compared to when untreated cells are used
• following pIpC treatment, the total number of cycling hematopoietic stem cells compared to in untreated mice
|
|
• the proportion of quiescent (G0) hematopoietic stem cells in the bone marrow of pIpC-treated mice is increased 17-fold compared with untreated controls
• following serum and cytokine withdrawal, the hematopoietic stem cells in the bone marrow of pIpC-treated mice exhibit increased apoptosis compared with untreated controls
• following induction with pIpC, hematopoietic stem cells used in serial transplantation experiments exhaust earlier than wild-type cells
|
|
• following induction with pIpC and treatment with ENU, latency is shortened and a higher proportion of mice develop malignacy compared to control mice
|
|
• following induction with pIpC and treatment with ENU, mice develop aggressive T cell leukemias with high blast counts and replacement of normal bone marrow with CD4+ CD8+ lymphoblasts unlike in control mice
|
|
• following induction with pIpC and treatment with ENU, latency is shortened and a higher proportion of mice develop malignacy compared to control mice
|
| N |
• T cell development is normal following pIpC induction
|
|
• in repopulation assays, bone marrow cells from pIpC treated lead to reduced donor-derived lymphocyte numbers compared to when untreated cells are used
|
|
• following pIpC treatment, myeloid progenitors are increased compared to in untreated mice
|
|
• mild to moderate following pIpC treatment
|
|
• mild to moderate following pIpC treatment
|
|
• B cells are gradually lost following pIpC treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at day 6 after PI-PC treatment, mutant mice show impaired erythropoiesis in bone marrow and spleen; a 4-fold reduction of mature erythroid cells is noted in speen
|
|
• both mutant and control mice show a 25% reduction in hematocrit levels at 6 days after PI-PC treatment; however, control animals are able to normalize this defect 1 week later, whereas mutant mice remain anemic
|
|
• adult mutant mice exhibit impaired megakaryopoiesis and erythropoiesis with loss of early progenitor cells in both lineages
|
|
• mutants display a 50% reduction in total bone marrow cellularity relative to control mice
|
|
• megakaryocytes from mutant bone marrows are larger (~2-fold increase in diameter) and appear dysplastic with hyperlobulated nuclei
• megakaryocytes are virtually absent from the spleens of mutant mice; however, megakaryocytes in deleted bone marrows retain the ability to shed platelets in response to thrombocytopenia
• in mutant bone marrow, CFU-S12 colonies are reduced 2-fold and appear smaller and pale with no erythroid or megakaryocytic component
|
|
• in vitro, mutant bone marrows and spleens are devoid of megakaryocyte progenitors
|
|
• at 6 days after PI-PC treatment, mutant bone marrows and spleens are devoid of erythroid progenitors (BFU-E)
• in contrast, the frequency and behavior of myeloid CFCs is not significantly affected
|
|
• after 6 days and 3 injections of PI-PC, mutant mice continue to display decreased platelet counts whereas increased megakaryocytopoiesis in the spleen has normalized platelet counts in control mice
• notably, mutant mice do recover completely from the acute fall in their white cell count
|
|
• megakaryocytes are virtually absent from the spleens of mutant mice
|
|
• megakaryocytes are virtually absent from the spleens of mutant mice
|
|
• flushed bone marrow samples from mutant mice are pale relative to control samples
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• thymocyte growth stimulated
• conversion of double negative to double positive lymphocytes impaired
|
|
• conversion of double negative to double positive lymphocytes impaired
|
|
• increased proportion of immature myeloid cells in bone marrow
|
|
• differentiation of granulocytes in bone marrow blocked
|
|
• moderate reduction in CD4 single positive cells
|
|
• increased incidence of CD8 single positive cells at the expense of CD4 positive cells
|
|
• thymocyte growth stimulated
• conversion of double negative to double positive lymphocytes impaired
|
|
• conversion of double negative to double positive lymphocytes impaired
|
|
• increased proportion of immature myeloid cells in bone marrow
|
|
• differentiation of granulocytes in bone marrow blocked
|
|
• moderate reduction in CD4 single positive cells
|
|
• increased incidence of CD8 single positive cells at the expense of CD4 positive cells
|
|
• start to develop T-lympoid leukemia/lymphoma about 6 months after conditional activation of the gene insert
• 39% die over the 7 months following appearance of tumors
|
|
• neoplastic cells from thymus are found infiltrating spleen, liver, and bone marrow
|
|
• differentiation of granulocytes in bone marrow blocked
|
|
• 39% die over the 7 months following appearance of tumors
• start to develop T-lympoid leukemia/lymphoma about 6 months after conditional activation of the gene insert
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• when treated at day 2 or 3 with pIpC, the median age of death is 16 days with distended abdomens, pale footpads, hunched posture, and ruffled fur
• untreated mice exhibit a median age of death of 95 days do to the leakiness of the cre transgene
|
|
• when treated at day 2 or 3 with pIpC, spleens are 12.8-fold larger than wild-type due to increased proliferation without decreased apoptotic rates
|
|
• when treated at day 2 or 3 with pIpC, blood smears contain an abnormal presence of immature blast cells
|
|
• when treated at day 2 or 3 with pIpC, red pulp is expanded with immature myeloid cells that are 30% to 50% positive for stem cell markers
|
|
• 2.1+/-0.5x106 per ul compared to 6.4+/-1.5x106 per ul in wild-type mice when treated at day 2 or 3 with pIpC
|
|
• 15+/-3% compared to 37+/-7% in wild-type mice when treated at day 2 or 3 with pIpC
|
|
• 515+/-223x103 per ul compared to 399+/-149x103 per ul in wild-type mice when treated at day 2 or 3 with pIpC
|
|
• 90+/-68x103 per ul compared to 3.4+/-1.5x103 per ul in wild-type mice when treated at day 2 or 3 with pIpC
|
|
• when treated at day 2 or 3 with pIpC, red pulp is expanded with immature myeloid cells that are 30% to 50% positive for stem cell markers
|
|
• when treated at day 2 or 3 with pIpC, mice develop leukemias and when transplanted into recipient mice are associated with leukemic proliferation
|
|
• when treated at day 2 or 3 with pIpC, livers are 3.3-fold larger than wild-type due to increased proliferation without decreased apoptotic rates
|
|
• when treated at day 2 or 3 with pIpC, spleens are 12.8-fold larger than wild-type due to increased proliferation without decreased apoptotic rates
|
|
• when treated at day 2 or 3 with pIpC, red pulp is expanded with immature myeloid cells that are 30% to 50% positive for stem cell markers
|
|
• 90+/-68x103 per ul compared to 3.4+/-1.5x103 per ul in wild-type mice when treated at day 2 or 3 with pIpC
|
|
• when treated at day 2 or 3 with pIpC, red pulp is expanded with immature myeloid cells that are 30% to 50% positive for stem cell markers
|
|
• when treated at day 2 or 3 with pIpC, lymphoid follicles is decreased
|
|
• when treated at day 2 or 3 with pIpC, livers are 3.3-fold larger than wild-type due to increased proliferation without decreased apoptotic rates
|
|
• when treated at day 2 or 3 with pIpC, spleens are 12.8-fold larger than wild-type due to increased proliferation without decreased apoptotic rates
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice treated with pIpC to induce cre expression develop spontaneous T-cell leukemia (T-ALL), with a latency of development of 122-281 days following pIpC treatment
• leukemic cells infiltrate the bone marrow, spleen, liver, and kidney infiltrates comprise a mixture of mature lymphoid cells with open chromatin and cells with blastic appearance and prominent nucleoli
• leukemias are phenotypically heterogenous
|
|
• 7-8 week old mice treated with pIpC to induce cre expression exhibit a 7-10-fold decrease in the numbers of thymocytes
|
|
• mice treated with pIpC to induce cre expression exhibit an enlarged spleen
|
|
• 7-8 week old mice treated with pIpC to induce cre expression exhibit an accumulation of immature CD4-CD8- cell population
|
|
• 7-8 week old mice treated with pIpC to induce cre expression exhibit a decrease in CD4+CD8+ cells
|
|
• mice treated with pIpC to induce cre expression exhibit enlarged lymph nodes
|
|
• 7-8 week old mice treated with pIpC to induce cre expression exhibit a 7-10-fold decrease in the numbers of thymocytes
|
|
• mice treated with pIpC to induce cre expression exhibit an enlarged spleen
|
|
• 7-8 week old mice treated with pIpC to induce cre expression exhibit an accumulation of immature CD4-CD8- cell population
|
|
• 7-8 week old mice treated with pIpC to induce cre expression exhibit a decrease in CD4+CD8+ cells
|
|
• 7-8 week old mice treated with pIpC to induce cre expression exhibit a 7-10-fold decrease in the numbers of thymocytes
|
|
• mice treated with pIpC to induce cre expression exhibit an enlarged spleen
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| acute lymphoblastic leukemia | DOID:9952 |
OMIM:247640 OMIM:613065 |
J:182211 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice treated with pIpC to induce cre expression develop spontaneous T-cell leukemia (T-ALL), with a latency of development of 122-281 days following pIpC treatment
• leukemic cells infiltrate the bone marrow, spleen, liver, and kidney infiltrates comprise a mixture of mature lymphoid cells with open chromatin and cells with blastic appearance and prominent nucleoli
• leukemias are phenotypically heterogenous
|
|
• 7-8 week old mice treated with pIpC to induce cre expression exhibit a 7-10-fold decrease in the numbers of thymocytes
|
|
• mice treated with pIpC to induce cre expression exhibit an enlarged spleen
|
|
• 7-8 week old mice treated with pIpC to induce cre expression exhibit an accumulation of immature CD4-CD8- cell population
|
|
• 7-8 week old mice treated with pIpC to induce cre expression exhibit a decrease in CD4+CD8+ cells
|
|
• mice treated with pIpC to induce cre expression exhibit enlarged lymph nodes
|
|
• 7-8 week old mice treated with pIpC to induce cre expression exhibit a 7-10-fold decrease in the numbers of thymocytes
|
|
• mice treated with pIpC to induce cre expression exhibit an enlarged spleen
|
|
• 7-8 week old mice treated with pIpC to induce cre expression exhibit an accumulation of immature CD4-CD8- cell population
|
|
• 7-8 week old mice treated with pIpC to induce cre expression exhibit a decrease in CD4+CD8+ cells
|
|
• 7-8 week old mice treated with pIpC to induce cre expression exhibit a 7-10-fold decrease in the numbers of thymocytes
|
|
• mice treated with pIpC to induce cre expression exhibit an enlarged spleen
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| acute lymphoblastic leukemia | DOID:9952 |
OMIM:247640 OMIM:613065 |
J:182211 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• with pIpC treatement, B cell development in bone marrow is severely impaired; pro-B, pre-B, and immunoglobulin IgM+ B cells are drastically reduced in number, whereas prepro-B cell numbers are increased with pIpC treatment
• prepro-B cells express elevated levels of T cell-specific target genes and appear to aberrantly committed to the T cell lineage despite B220 expression; in culture, pIpC-treated cells lose B220 expression and differentiate into CD4/8 double positive T cells
• inhibition of Notch signaling by treatment with a gamma secretase inhibitor (GSI) rescues B or T cell commitment abnormalities
|
|
• accumulation of extrathymic double-positive T cells is seen in bone marrow of pIpC treated mice, with these cells accounting for ~30% of bone marrow mononuclear cells 1 month after pIpC treatment; these DP T cells are not found in spleen or Peyer's patches
|
|
• after injection of polyinosinic:polycytidylic acid (pIpC) at 2 week intervals starting at 3 weeks of age to induce cre expression, significant decline in white blood cells is observed relative to untreated controls
|
|
• reduction in B220+ B cells with polyinosinic:polycytidylic acid-induced cre induction
• however, T cell numbers remain similar to controls
|
|
• with pIpC treatment, slightly increased numbers are observed with pIpC treatment; numbers of common lyphoid progenitor (CLP) cells are also slightly elevated
|
| N |
• slight decrease in double-negative 3 (DN3) and double-negative 4 (DN4) thymocyte populations is seen, but proportions of CD4 single-positive, CD8 single-positive, and CD4/8 double-positive T cells are comparable to control mice after pIpC treatment
|
|
• with pIpC treatement, B cell development in bone marrow is severely impaired; pro-B, pre-B, and immunoglobulin IgM+ B cells are drastically reduced in number, whereas prepro-B cell numbers are increased with pIpC treatment
• prepro-B cells express elevated levels of T cell-specific target genes and appear to aberrantly committed to the T cell lineage despite B220 expression; in culture, pIpC-treated cells lose B220 expression and differentiate into CD4/8 double positive T cells
• inhibition of Notch signaling by treatment with a gamma secretase inhibitor (GSI) rescues B or T cell commitment abnormalities
|
|
• accumulation of extrathymic double-positive T cells is seen in bone marrow of pIpC treated mice, with these cells accounting for ~30% of bone marrow mononuclear cells 1 month after pIpC treatment; these DP T cells are not found in spleen or Peyer's patches
|
|
• after injection of polyinosinic:polycytidylic acid (pIpC) at 2 week intervals starting at 3 weeks of age to induce cre expression, significant decline in white blood cells is observed relative to untreated controls
|
|
• reduction in B220+ B cells with polyinosinic:polycytidylic acid-induced cre induction
• however, T cell numbers remain similar to controls
|
|
• when cells from these mice are transferred to lethally irradiated recipients, upon pIpC treatment, donor-derived double positive T cells accumulate in bone marrow and peripheral blood
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following pIpC treatment 14 of 22 mice developed acute leukemia
• median latency for leukemia development was 131 days
• infiltration of the bone marrow, spleen and liver with immature hematopoietic cells is seen in moribund mice
• mice may develop either acute myeloid leukemia or acute lymphoblastic leukemia
• gene expression profiles in mice with acute lymphoblastic leukemia recapitulate gene expression profiles seen in human acute lymphoid leukemia
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| acute lymphoblastic leukemia | DOID:9952 |
OMIM:247640 OMIM:613065 |
J:140628 | |
| acute myeloid leukemia | DOID:9119 |
OMIM:601626 |
J:140628 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die within 14-18 days of final injection of polyI:polyC used to induce transgene expression and subsequent Ctnnb1 deletion; no treated controls die
|
|
• some induced mice show disrupted bone architecture with enhanced trabecular bone structures
|
|
• some induced mutants display hepatoblastoma
|
|
• some induced mice display skin fibrosis
|
|
• some induced mutants display hepatoblastoma
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die within 14-18 days of final injection of polyI:polyC used to induce transgene expression and subsequent Ctnnb1 deletion; no treated controls die
|
|
• some induced mice show disrupted bone architecture with enhanced trabecular bone structures
|
|
• some induced mutants display hepatoblastoma
|
|
• some induced mice display skin fibrosis
|
|
• some induced mutants display hepatoblastoma
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• phenotype examined after cre activation by IP injection of IFN-alpha
• slightly reduced percentage of B220+ cells in the bone marrow of the femur
|
|
• fraction E cells are reduced 40% in bone marrow
• failure to retain immature B cells in bone marrow to complete maturity
|
|
• 63% reduction in numbers of fraction F cells in the bone marrow
|
|
• phenotype examined after cre activation by IP injection of IFN-alpha
|
|
• modestly increased in the spleen
|
|
• dramatically increased number of fraction E cells in the circulation (30% vs 15%)
|
|
• circulating fraction F cells elevated about 3 fold
|
|
• phenotype examined after cre activation by IP injection of IFN-alpha
• impaired primary and 5 fold reduced secondary IgG1 response to the T cell dependent antigen NP-CG
• response to T-cell independent antigens is normal
|
|
• phenotype examined after cre activation by IP injection of IFN-alpha
• slightly reduced percentage of B220+ cells in the bone marrow of the femur
|
|
• fraction E cells are reduced 40% in bone marrow
• failure to retain immature B cells in bone marrow to complete maturity
|
|
• 63% reduction in numbers of fraction F cells in the bone marrow
|
|
• phenotype examined after cre activation by IP injection of IFN-alpha
|
|
• modestly increased in the spleen
|
|
• dramatically increased number of fraction E cells in the circulation (30% vs 15%)
|
|
• circulating fraction F cells elevated about 3 fold
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• pIpC-treated mice exhibit normal adult hematopoiesis
|
| N |
• pIpC-treated mice exhibit normal B cell and T cell development
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• after pIpC injection, the number of colony forming unit cultures in the peripheral blood is significantly but variably increased compared to controls
• the degree of increase in colony forming unit cultures correlates to the extent of recombination in bone marrow nonhematopoietic cells
|
|
• after pIpC injection, progenitor cell numbers and total cell numbers are decreased compared to controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• moderately reduced neutrophile counts
|
|
• dramatically reduced platelet counts
• platelet recovery after about 4 weeks
|
|
• moderately reduced neutrophile counts
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• platelet thrombus formation is severely impaired ex vivo after treatment of platelets with polyinosinic-polycytidylic acid (PIPC) to induce recombination
• however, initial adhesion of platelets is similar to wild-type
|
|
• serotonin secretion induced by U46619 plus adrenaline or Par-4 peptide exposure is significantly decreased compared to wild-type cells
• however, thrombin-induced serotonin secretion is not impaired
• absence of a shape change in response to low concentration of stimuli compared to wild-type following polyinosinic-polycytidylic acid (PIPC) treatment
• however, shape change is induced with high concentration of stimuli
• potency of agonists to induce aggregation is reduced but aggregation occurs at all agonist concentrations
|
|
• potency of agonists to induce aggregation is reduced but aggregation occurs at all agonist concentrations
|
|
• very large increase in bleeding time in interferon-responsive tissues
• when bone marrow-derived cells PIPC-treated mice are transplanted into irradiated wild-type mice, 4 weeks later mice have greatly prolonged bleeding times (>20 minutes) compared with mice receiving cells from noninduced controls
|
|
• serotonin secretion induced by U46619 plus adrenaline or Par-4 peptide exposure is significantly decreased compared to wild-type cells
• however, thrombin-induced serotonin secretion is not impaired
• absence of a shape change in response to low concentration of stimuli compared to wild-type following polyinosinic-polycytidylic acid (PIPC) treatment
• however, shape change is induced with high concentration of stimuli
• potency of agonists to induce aggregation is reduced but aggregation occurs at all agonist concentrations
|
|
• potency of agonists to induce aggregation is reduced but aggregation occurs at all agonist concentrations
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• development of hemangiomas leads to premature death becoming significant at ~55 weeks of age with induced cre expression
|
|
• when mice are treated with poly(I:C) to induce cre expression, 100% of females display mild hemangiomas in the uterus and perirenal fat by 60 weeks of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• resulting from stress erythropoiesis after Poly(I:C) treatment
|
|
• adults at 8-12 weeks of age were assessed after being injected with 300 ug Poly(I:C) every other day for 5 days and were found to have suppressed basal erythropoiesis with severe anemia, thrombocytopenia, and leukopenia, with very low CD45- erythroid and CD45+ non-erythroid cell counts in bone marrow, but progression between precursor stages is not affected, and stress erythropoiesis is found with markedly increased spleen size, increased red pulp, increased BFU-E and CFU-E, increased erythroblasts, and reticulocytosis
|
|
• after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• in spleen after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• resulting from stress erythropoiesis after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• after Poly(I:C) treatment
|
|
• resulting from stress erythropoiesis after Poly(I:C) treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in an in vitro hematopoietic progenitor assay, spleen samples from pIpC-treated mice produce more granulocyte/macrophages, erythroid cells and immature red blood cells compared with wild-type spleen samples
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• immature dendritic cells from pIpC-treated mice exhibit reduced spreading on a fibronectin coated surface, rosette podosome formation, ability to degrade the extracellular matrix and migrate through matrigel-coated filters compared with wild-type cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• fibroblasts isolated from floxed/Mx-Cre mice exhibit cell cycle defects when the cre transgene is induced
• results suggest that this protein is required for S phase and is required for the correct progression of DNA replication
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die within days of pIpC treatment unlike similarly treated wild-type mice
• however, pIpC-treated mice injected with wild-type bone marrow survive
|
|
• myelo-erythroid progenitor cells from pIpC-treated mice exhibit reduced proliferation and a 2.6-fold reduction in re-entry into the cell cycle following serum and cytokine starvation compared to wild-type cells
• however, the composition of cell populations produced is normal
|
|
• 11 days after pIpC, treatment common myeloid progenitors, granulocyte-progenitors, and megakaryocyte-erythrocyte progenitors are decreased 1.4- to 4-fold compared to in wild-type mice
• cultured bone marrow cells of pIpC-treated mice exhibit a 2- to 5-fold decrease in myeloid colonies compared to wild-type cells
|
|
• pIpC-treated mice exhibit bone marrow cytopenia unlike in wild-type mice
|
|
• 11 days after pIpC treatment, lymphocyte progenitor cells are decreased 1.4- to 4-fold compared to in wild-type mice
• cultured bone marrow cells of pIpC-treated mice exhibit a 2- to 5-fold decrease in lymphoid colonies compared to wild-type cells
|
|
• 11 days after pIpC, treatment common myeloid progenitors, granulocyte-progenitors, and megakaryocyte-erythrocyte progenitors are decreased 1.4- to 4-fold compared to in wild-type mice
• cultured bone marrow cells of pIpC-treated mice exhibit a 2- to 5-fold decrease in erythroid colonies compared to wild-type cells
|
|
• pIpC-treated mice exhibit a loss of hematopoietic stem cell (HSC) renewal followed by an increase in HSC proliferation and subsequent depletion of these cells unlike in wild-type mice
|
|
• pIpC-treated mice exhibit a cell-intrinsic loss of hematopoietic stem cell-enriched KSL populations and loss of hematopoietic stem cell activity unlike similarly treated wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• poly (IC) treated mice develop multilineage cytopenia
|
|
• mice develop low-level myeloid dysplasia after poly (IC) treatment
|
|
• mice develop thrombocytopenia after poly (IC) treatment
|
|
• mice exhibit an increased percentage of myeloid cells and increased myeloid colony formation after poly (IC) treatment
|
|
• mice develop low-level erythroid dysplasia after poly (IC) treatment
|
|
• one mouse treated with ENU after poly (IC) treatment developed acute myeloid leukemia
• mice treated with ENU after poly (IC) treatment exhibit increased percentages of myeloid cells in the peripheral blood, enlarged spleen, and extramedullary hematopoiesis, occasional low-grade dysplasia in the erythroid and neutrophil lineages indicating the development of myeloproliferative neoplasm
|
| N |
• poly (IC) treated mice have a normal life span and do not develop frank leukemia within 1.5 years after poly (IC) treatment
|
|
• mice treated with ENU after poly (IC) treatment die prematurely with myeloid pathology
|
|
• one mouse treated with ENU after poly (IC) treatment developed acute myeloid leukemia
• mice treated with ENU after poly (IC) treatment exhibit increased percentages of myeloid cells in the peripheral blood, enlarged spleen, and extramedullary hematopoiesis, occasional low-grade dysplasia in the erythroid and neutrophil lineages indicating the development of myeloproliferative neoplasm
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pIpC-induced mice die prematurely but at an older age than induced conditional Krastm4Tyj mice
|
|
• mice induced with polyinosinic:polycytidylic acid (pIpC) develop a myelodysplastic syndrome/myeloproliferative neoplasm that is qualitatively similar to that seen in conditional Krastm4Tyj mice, but with a delayed onset
|
|
• dying pIpC-induced mice show splenomegaly
|
|
• hemoglobin levels decline over time in pIpC-induced mice
|
|
• white blood cell counts slowly rise over time in pIpC-induced mice
|
|
• expansion of immature myeloid cells in the bone marrow and spleen in pIpC-induced mice
|
|
• expansion of immature myeloid cells in the bone marrow of pIpC-induced mice
|
|
• dying pIpC-induced mice show splenomegaly
|
|
• white blood cell counts slowly rise over time in pIpC-induced mice
|
|
• dying pIpC-induced mice show splenomegaly
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• survival for around 35 days after pI-pC treatment
• survival of around 58 days even without pI-pC treatment
|
|
• 7 of 25 mice injected with pIpC develop thymic T cell lymphoblastic lymphomas
• 2 of 6 non pIpC treated mice show thymic lymphomas
|
|
• 10 of 17 mice injected with pIpC exhibit multiple nodules in the lungs consisting of proliferating type II penumocytes
• 5 of 6 non pIpC treated mice show pulmonary adenomas
|
|
• squamous papillomas
|
|
• 8 of 22 mice injected with pIpC develop squamous papillomas involving the esophageal mucosa
|
|
• 8 of 25 mice injected with pIpC develop squamous papillomas involving the oral mucosa
• 2 of 6 non-pIpC treated mice show oral squamous papillomas
|
|
• 12 of 19 mice injected with pIpC develop squamous papillomas involving the anal and vulvo-vaginal skin and 8 of 22 mice develop squamous papillomas involving the ear
• 2 of 6 non-pIpC treated mice show ear squamous papillomas
|
|
• mice injected with pIpC develop moderate to severe splenomegaly
|
|
• mice injected with pIpC develop moderate to severe splenomegaly
|
|
• develop lethal hematopoietic disease
|
|
• 4-7 week old mice injected with pIpC develop a myeloproliferative disorder
• bone marrow of mice injected with pIpC shows myelomonocytic expansion
• all mice that are not treated with pIpC also develop a hematopoietic disease, however these mice exhibit expression of the mutant Kras, indicating that most likely endogenous IFN expression is sufficient to induce the cre transgene
• bone marrow cells from pIpC injected mice readily form colonies, predominately monocyte colony-forming units (M-CFUs) in a growth factor-independent manner unlike controls
|
|
• myeloproliferative phenotype
• myeloid hyperplasia of bone marrow
|
|
• expansion of red pulp in spleen by granulocyte/monocyte lineages in 11 out of 16 cases
• erythroid expansion was seen in red pulp of spleen in 5 of 16 cases
• the liver shows perivascular and periportal infiltration by myeloid and erythroid cell populations
|
|
• mice injected with pIpC have a mean hematocrit of 27% compared with 45% in controls
|
|
• leukocytosis, usually involving increases in granulocytes, in both pIpC and non-pIpC treated mice
|
|
• leukocytosis in mice injected with pIpC is mainly due to an increase in granulocyte population
|
|
• mice injected with pIpC show expansion of the red pulp by varying degrees of granulocytic
|
|
• mice injected with pIpC develop moderate to severe splenomegaly
|
|
• 4-7 week old mice injected with pIpC develop a myeloproliferative disorder
• bone marrow of mice injected with pIpC shows myelomonocytic expansion
• all mice that are not treated with pIpC also develop a hematopoietic disease, however these mice exhibit expression of the mutant Kras, indicating that most likely endogenous IFN expression is sufficient to induce the cre transgene
• bone marrow cells from pIpC injected mice readily form colonies, predominately monocyte colony-forming units (M-CFUs) in a growth factor-independent manner unlike controls
|
|
• myeloproliferative phenotype
• myeloid hyperplasia of bone marrow
|
|
• leukocytosis, usually involving increases in granulocytes, in both pIpC and non-pIpC treated mice
|
|
• leukocytosis in mice injected with pIpC is mainly due to an increase in granulocyte population
|
|
• mice injected with pIpC show expansion of the red pulp by varying degrees of granulocytic
|
|
• 6 of 17 mice injected with pIpC develop nodal lymphoid hyperplasia
|
|
• perivascular and periportal infiltration in liver by myeloid and erythroid cells similar to what is seen in spleen
|
|
• ruffled fur
|
|
• 12 of 19 mice injected with pIpC develop squamous papillomas involving the anal and vulvo-vaginal skin and 8 of 22 mice develop squamous papillomas involving the ear
• 2 of 6 non-pIpC treated mice show ear squamous papillomas
|
|
• 8 of 22 mice injected with pIpC develop squamous papillomas involving the esophageal mucosa
|
|
• 8 of 25 mice injected with pIpC develop squamous papillomas involving the oral mucosa
• 2 of 6 non-pIpC treated mice show oral squamous papillomas
|
|
• 7 of 25 mice injected with pIpC develop thymic T cell lymphoblastic lymphomas
• 2 of 6 non pIpC treated mice show thymic lymphomas
|
|
• 10 of 17 mice injected with pIpC exhibit multiple nodules in the lungs consisting of proliferating type II penumocytes
• 5 of 6 non pIpC treated mice show pulmonary adenomas
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| juvenile myelomonocytic leukemia | DOID:0050458 |
OMIM:607785 |
J:88163 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutants injected with poly(I:C) to induce cre expression, exhibit 25% more platelets in the blood than controls
|
|
• collagen-induced platelet activation is enhanced in mutants injected with poly(I:C) to induce cre expression
|
|
• platelets of mutants injected with poly(I:C) to induce cre expression are induced to aggregate by a much lower level of collagen than is required to induce the same response by wild-type platelets
|
|
• collagen-induced platelet activation is enhanced in mutants injected with poly(I:C) to induce cre expression
|
|
• platelets of mutants injected with poly(I:C) to induce cre expression are induced to aggregate by a much lower level of collagen than is required to induce the same response by wild-type platelets
|
|
• mutants injected with poly(I:C) to induce cre expression have an average bleeding time that is shorter than in controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pIpC-induced mice die earlier than induced conditional Krastm1.1Khai mice
|
|
• mice induced with polyinosinic:polycytidylic acid (pIpC) develop a myelodysplastic syndrome/myeloproliferative neoplasm that is qualitatively similar to that seen in conditional Krastm1.1Khai mice, but with a faster onset
|
|
• dying pIpC-induced mice show splenomegaly
|
|
• expansion of immature myeloid cells in the bone marrow and spleen in pIpC-induced mice
|
|
• expansion of immature myeloid cells in the bone marrow of pIpC-induced mice
|
|
• dying pIpC-induced mice show splenomegaly
|
|
• dying pIpC-induced mice show splenomegaly
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• some intrauterine deaths occur between E14.5 and E16.5, but on a congenic background, some homozygous embryos surviving past E7.5 die at E12.5
|
|
• some intrauterine deaths occur at or before E7.5
|
|
• Background Sensitivity: at E14.5, limb maturation, hand, and digit maturation are abnormal; more apparent at time of death than on a congenic background
|
|
• at E14.5, digit maturation is abnormal
|
|
• Background Sensitivity: more obvious at time of death on mixed background versus congenic
|
| N |
• genitourinary system appears grossly normal at E14.5
|
| N |
• genitourinary system appears grossly normal at E14.5
|
| N |
• pulmonary system appears grossly normal at E14.5
|
| N |
• cardiovascular system appears grossly normal at E14.5
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Diamond-Blackfan anemia | DOID:1339 |
OMIM:PS105650 |
J:132057 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• after pIpC treatment
|
|
• after pIpC treatment
|
|
• after pIpC treatment, the number of DN3 and DN4 T cells is decreased 3-fold compared to in wild-type mice
|
|
• after pIpC treatment, the number of DN1 increased 3-fold compared to in wild-type mice
|
|
• after pIpC treatment, T cell maturation is blocked at the DN2 to DN3 stage
|
|
• following pIpC treatment, myeloid progenitors are increased compared to in untreated mice
|
|
• two weeks after pIpC treatment
|
|
• following pIpC treatment, bone marrow B cells are lost unlike in untreated controls
|
|
• following pIpC treatment, the number of long-term repopulating hematopoietic stem cells is decreased compared to in untreated controls
|
|
• following pIpC treatment, the hematopoietic stem cells- enriched LKS+ population is increased unlike in untreated controls
|
|
• all mice die prematurely after receiving ENU, within 15 months after poly (IC) treatment, with myeloid pathology including increased percentages of myeloid cells in the peripheral blood, enlarged spleen, and extramedullary hematopoiesis, occasional low-grade dysplasia in the erythroid and neutrophil lineages indicating the development of myeloproliferative neoplasm
|
|
• after pIpC treatment
|
|
• after pIpC treatment
|
|
• after pIpC treatment, the number of DN3 and DN4 T cells is decreased 3-fold compared to in wild-type mice
|
|
• after pIpC treatment, the number of DN1 increased 3-fold compared to in wild-type mice
|
|
• after pIpC treatment, T cell maturation is blocked at the DN2 to DN3 stage
|
|
• following pIpC treatment, bone marrow B cells are lost unlike in untreated controls
|
|
• all mice die prematurely after receiving ENU, within 15 months after poly (IC) treatment
|
|
• all mice die prematurely after receiving ENU, within 15 months after poly (IC) treatment, with myeloid pathology including increased percentages of myeloid cells in the peripheral blood, enlarged spleen, and extramedullary hematopoiesis, occasional low-grade dysplasia in the erythroid and neutrophil lineages indicating the development of myeloproliferative neoplasm
|
|
• after pIpC treatment
|
|
• after pIpC treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• after pIpC treatment, thymus weight is less than in wild-type mice but greater than in Runx1tm3Spe/Runx1tm3Spe Tg(Mx1-cre)1Cgn mice
|
|
• after pIpC treatment
|
|
• after pIpC treatment, the number of Gr-1+Mac1+ cells in the spleen is increased 8-fold compared to in wild-type mice
|
|
• after pIpC treatment, the B cell compartment is reduced in the spleen and bone marrow
|
|
• after pIpC treatment, thymus weight is less than in wild-type mice but greater than in Runx1tm3Spe/Runx1tm3Spe Tg(Mx1-cre)1Cgn mice
|
|
• after pIpC treatment
|
|
• after pIpC treatment, the number of Gr-1+Mac1+ cells in the spleen is increased 8-fold compared to in wild-type mice
|
|
• after pIpC treatment, the B cell compartment is reduced in the spleen and bone marrow
|
|
• after pIpC treatment, thymus weight is less than in wild-type mice but greater than in Runx1tm3Spe/Runx1tm3Spe Tg(Mx1-cre)1Cgn mice
|
|
• after pIpC treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• accumulation of mature T cells in the thymus without changes in other thymic subsets
|
|
• mice exhibit a reduction in NK cell egression from the peripheral lymph nodes compared with wild-type mice
|
|
• accumulation of mature T cells in the thymus without changes in other thymic subsets
|
|
• blood and lymph B cell counts are significantly lower than controls
• however, the number of B cells in the spleen and lymph node is normal
|
|
• in the spleen and lymph
|
|
• in bone marrow and slightly in the lymph nodes
|
|
• mice treated with polyinosine polycytidylic acid at P3 - 5 display markedly reduced T cell number in blood and lymph
• however, spleen and lymph node T cell numbers are normal
|
|
• undetectable levels of sphingosine-1-phosphate (S1P) in the plasma and lymph
|
|
• accumulation of mature T cells in the thymus without changes in other thymic subsets
|
|
• mice exhibit a reduction in NK cell egression from the peripheral lymph nodes compared with wild-type mice
|
|
• accumulation of mature T cells in the thymus without changes in other thymic subsets
|
|
• decrease in the number of mature B cells in the bone marrow
• however, immature cell numbers are similar to controls
|
|
• blood and lymph B cell counts are significantly lower than controls
• however, the number of B cells in the spleen and lymph node is normal
|
|
• in the spleen and lymph
|
|
• in bone marrow and slightly in the lymph nodes
|
|
• mice treated with polyinosine polycytidylic acid at P3 - 5 display markedly reduced T cell number in blood and lymph
• however, spleen and lymph node T cell numbers are normal
|
|
• accumulation of mature T cells in the thymus without changes in other thymic subsets
|
|
• after ovalbumin and CFA challenge, pIpC-treated mice exhibit bleeding in the draining peripheral lymph nodes and increased permeability to FITC-dextran unlike control mice
• however, pIpC-treated mice do not exhibit spontaneous bleeding into mucosal lymph nodes
|
|
• after ovalbumin and CFA challenge, pIpC-treated mice exhibit bleeding in the draining peripheral lymph nodes and increased permeability to FITC-dextran unlike control mice
• however, pIpC-treated mice do not exhibit spontaneous bleeding into mucosal lymph nodes and transfusion with wild-type platelets reduces vascular leakage of FITC-dextran
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• induction of cre at 10 days of age prevents the diffuse bone loss and focal cystic changes characteristic of mice homozygote for the Sh3bp2tm1Bjro allele
|
|
• bone marrow cells fail to differentiate into osteoclasts in vitro
|
|
• a dramatic reduction in the number of TRAP+ cells is found iin the proximal humerus and distal femur
|
|
• bone marrow cells fail to differentiate into osteoclasts in vitro
|
|
• widespread inflammation is observed
|
|
• a dramatic reduction in the number of TRAP+ cells is found iin the proximal humerus and distal femur
|
|
• widespread inflammation is observed
|
|
• widespread inflammation is observed
|
|
• widespread inflammation is observed
|
|
• widespread inflammation is observed
|
|
• widespread inflammation is observed
|
|
• widespread inflammation is observed
|
|
• bone marrow cells fail to differentiate into osteoclasts in vitro
|
|
• a dramatic reduction in the number of TRAP+ cells is found iin the proximal humerus and distal femur
|
|
• bone marrow cells fail to differentiate into osteoclasts in vitro
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice develop multiple polyps in the small intestine one month after completion of pIpC injection to induce Cre expression
• polyps show a large excess of crypt-like units at their base and aberrant positioning of crypts along the edges of villi
• overgrowth and insertions of stromal cells from the base of the polypoid mass are seen in the small intestine one month after completion of pIpC injection to induce Cre expression
• intestinal stem cells exhibit increased proliferation due to Akt activation and nuclear localization of beta-catenin resulting in an increase of intestinal stem cells in the crypts
• these excess stem cells initiate de novo crypt formation and crypt fission at a higher rate than in controls
|
|
• mice injected with pIpC to induce Pten deletion, develop myeloproliferative disease and T-cell acute lymphoblastic leukemia
|
|
• mice injected with pIpC to induce Pten deletion have an enlarged thymus
|
|
• mice injected with pIpC to induce Pten deletion have an enlarged spleen
|
|
• mean survival time of mice injected with pIpC to induce Pten deletion is 35 days
|
|
• mice injected with pIpC to induce Pten deletion have an enlarged thymus
|
|
• mice injected with pIpC to induce Pten deletion have an enlarged spleen
|
|
• mice injected with pIpC to induce Pten deletion have an enlarged thymus
|
|
• mice injected with pIpC to induce Pten deletion have an enlarged spleen
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| acute lymphoblastic leukemia | DOID:9952 |
OMIM:247640 OMIM:613065 |
J:169097 | |
| Cowden syndrome | DOID:6457 |
OMIM:PS158350 |
J:118329 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at 18 weeks in pIpC-treated mice
|
|
• reduced frequency and absolute number of LSK cells as early as 4 weeks in pIpC-treated mice
• reduced overall numbers of hematopoietic stem cells at 18 weeks in pIpC-treated mice
|
|
• at 18 weeks in pIpC-treated mice
|
|
• at 18 weeks in pIpC-treated mice
|
|
• in reconstitution and replicative stress assays, pIpC-treated hematopoietic stem cells exhibit impaired engraftment and functionality with reduced production of myeloid lineages and a bias toward differentiation compared with control cells
|
| N |
• pIpC-treated mice exhibit normal frequencies of mature myeloid cell types and B and T cells in the bone marrow and spleen
|
|
• at 18 weeks in pIpC-treated mice
|
|
• at 18 weeks in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice survive for a median of 84 days after pIpC injection
|
|
• increase in the number of proliferating splenocytes in pIpC treated mice; most of these proliferating cells are Mac1+/Gr1 lo or Ter119+
|
|
• spleens of pIpC-treated moribund mice are massively enlarged
(J:87429)
• in pIpC treated mice
(J:115071)
|
|
• mice treated with pIpC show large numbers of proliferating splenic Ter199+ cells, indicating that erythropoiesis is ineffective
(J:87429)
• the erythroid progenitor compartment is massively expanded in the spleen of pIpC treated mice
(J:115071)
• pIpC treated mice show normal numbers of early erythroid cells in the bone marrow but a paucity of all the more mature TER119 hi populations, indicating an inefficient transition from TER119- to TER119 hi stages of erythropoiesis
(J:115071)
• bone marrow from pIpC treated mice forms abnormally large BFU-E colonies characterized by both erythropoietin-independent growth and hypersensitivity to erythropoietin
(J:115071)
• spleen of pIpC treated mice contains increase of immature CD71 hi TER119-/lo cells and large numbers of TER119 hi erythroblasts
(J:115071)
|
|
• pIpC injected mice develop a myeloproliferative disease with excess monocytes
• bone marrow mononuclear cells from pIpC treated mice form significant numbers of colony-forming unit granulocyte-macrophage (CFU-GM) colonies in the absence of exogenous cytokines while wild-type cells do not
• CFU-GM shows an increased proliferative response without added cytokines (9-fold) or to GM-CSF (19-fold increase) or IL-3 (37-fold increase)
|
|
• mice show abundant myeloid cells at various stages of differentiation after pIpC injection
|
|
• pups injected with pIpC develop anemia
(J:87429)
• however, normal platelet counts are seen in pIpC injected mice
(J:87429)
|
|
• in pIpC treated mice
|
|
• in pIpC treated mice
|
|
• in pIpC treated mice
|
|
• pups injected with pIpC at 21 days of age develop progressive leukocytosis that is evident 3 weeks after pIpC injection
|
|
• mice show an expanded population of Mac-1+, Gr-1 lo cells, indicating an expansion of immature monocytic cells
|
|
• in pIpC treated mice
|
|
• increase in the number of proliferating splenocytes in pIpC treated mice; most of these proliferating cells are Mac1+/Gr1 lo or Ter119+
|
|
• spleens of pIpC-treated moribund mice are massively enlarged
(J:87429)
• in pIpC treated mice
(J:115071)
|
|
• pIpC injected mice develop a myeloproliferative disease with excess monocytes
• bone marrow mononuclear cells from pIpC treated mice form significant numbers of colony-forming unit granulocyte-macrophage (CFU-GM) colonies in the absence of exogenous cytokines while wild-type cells do not
• CFU-GM shows an increased proliferative response without added cytokines (9-fold) or to GM-CSF (19-fold increase) or IL-3 (37-fold increase)
|
|
• mice show abundant myeloid cells at various stages of differentiation after pIpC injection
|
|
• pups injected with pIpC at 21 days of age develop progressive leukocytosis that is evident 3 weeks after pIpC injection
|
|
• mice show an expanded population of Mac-1+, Gr-1 lo cells, indicating an expansion of immature monocytic cells
|
|
• pIpC injected mice show moderate hepatomegaly with myeloid infiltration, particularly in periportal areas
|
|
• increase in the number of proliferating splenocytes in pIpC treated mice; most of these proliferating cells are Mac1+/Gr1 lo or Ter119+
|
|
• serum erythropoietin levels are increased in proportion to anemia in pIpC treated mice
|
|
• pIpC injected mice show moderate hepatomegaly with myeloid infiltration, particularly in periportal areas
|
|
• spleens of pIpC-treated moribund mice are massively enlarged
(J:87429)
• in pIpC treated mice
(J:115071)
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| NOT | acute myeloid leukemia | DOID:9119 |
OMIM:601626 |
J:87429 |
| juvenile myelomonocytic leukemia | DOID:0050458 |
OMIM:607785 |
J:87429 , J:115071 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• cellularity is reduced at 4 days after induction with poly(I:C)
• cell numbers continue to drop over a 3 month period
|
|
• bone marrow progenitor cells with a decreased tendency to develop into macrophage and dendritic cells after induction with poly(I:C)
• progenitors have reduced in vitro colony forming ability
|
|
• cellularity of bone marrow is reduced at 4 days after induction with poly(I:C)
• cell numbers continue to drop over a 3 month period
|
|
• RBC volume in peripheral blood is significantly reduced up to 6 days after induction with poly(I:C)
|
|
• cellularity is reduced at 4 days after induction with poly(I:C) but not significantly
• cell numbers continue to drop over a 3 month period
|
|
• cellularity is reduced at 4 days after induction with poly(I:C)
• cell numbers continue to drop over a 3 month period
|
|
• cellularity is reduced at 4 days after induction with poly(I:C) but not significantly
• cell numbers continue to drop over a 3 month period
|
|
• cellularity is reduced at 4 days after induction with poly(I:C)
• cell numbers continue to drop over a 3 month period
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• hepatocytes with a disrupted alleles proliferate more slowly than those with an intact alleles
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following induction of cre expression with polyIC, plasma cholesterol levels are reduced by 60%
|
|
• following polyIC induction, plasma HDL levels are reduced by 50%
|
|
• following polyIC induction, plasma IDL and LDL levels are almost undetectable
|
|
• following polyIC induction, plasma VLDL levels are almost undetectable
|
|
• following polyIC induction, plasma triglyceride levels are reduced by 45%
|
|
• following polyIC induction, plasma apoB-100 levels are not detectable
• following polyIC induction, plasma apoB-48 levels are reduced by ~65%
|
|
• following polyIC induction, hepatic cholesterol levels are increased by 65%
|
|
• following polyIC induction, hepatic triglyceride levels are increased 2.5-fold
|
|
• following polyIC induction, mutant liver weights are increased while body weights remain normal
|
|
• following polyIC induction, hepatic cholesterol levels are increased by 65%
|
|
• following polyIC induction, hepatic triglyceride levels are increased 2.5-fold
|
|
• following polyIC induction, apoB-100 is nearly absent in hepatic microsomes while apoB-48 remains unaffected
• following polyIC induction, no changes are observed in the levels of microsomal luminal chaparone proteins or cytosolic heat shock proteins
• following polyIC induction, hepatic secretion of apoB-100 is blocked without causing apoB to accumulate in the hepatic ER
|
|
• following polyIC induction, mutant liver weights are increased while body weights remain normal
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in pIpC-treated mice
|
|
• germinal center B cells in pIpC-treated mice exhibit a tendency to segregate from wild-type germinal center B cells
|
|
• in mucosal germinal centers when bone marrow cells are used to reconstitute wild-type mice treated with pIpC
|
|
• in pIpC-treated mice
|
|
• germinal center B cells in pIpC-treated mice exhibit a tendency to segregate from wild-type germinal center B cells
|
|
• in mucosal germinal centers when bone marrow cells are used to reconstitute wild-type mice treated with pIpC
|
|
• in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in pIpC-treated mice
|
|
• megakaryocytes from pIpC-treated mice exhibit aberrant nuclear morphology and mitotic figures and are frequently found intra-vascular or extravasating into bone marrow blood vessels and in the liver compared with control cells
|
|
• in the bone marrow of pIpC-treated mice without increased apoptosis
|
|
• 2-fold in pIpC-treated mice
|
|
• 6-fold in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice are moribund 9 days after pIpC treatment
|
|
• in pIpC-treated mice
|
|
• 20-fold in the bone marrow of pIpC-treated mice with increased apoptosis
|
|
• 5-fold in pIpC-treated mice
|
|
• 16-fold in pIpC-treated mice
|
|
• apoptotic megakaryocytes in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• lifespan after pIpC treatment is shorter than in controls and in mutant nice with no wild-type Pkn3 alleles
|
|
• develop myeloproliferative neoplasms in the spleen 2 weeks after pIpC treatment
|
|
• all eventually develop T cell acute lymphoblastic leukemia after pIpC treatment at 6 weeks of age
|
|
• at 2 weeks after pIpC treatment
|
|
• at 2 weeks after pIpC treatment
|
|
• increase in the number of hematopoietic stem cells in the spleen 2 weeks after pIpC treatment
|
|
• at 2 weeks after pIpC treatment
|
|
• at 2 weeks after pIpC treatment
|
|
• at 2 weeks after pIpC treatment
|
|
• at 2 weeks after pIpC treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• lifespan after pIpC treatment is shorter than in controls but longer than in mutant nice with one wild-type Pkn3 allele
|
|
• develop myeloproliferative neoplasms in the spleen 2 weeks after pIpC treatment
|
|
• all eventually develop T cell acute lymphoblastic leukemia after pIpC treatment at 6 weeks of age
|
|
• at 2 weeks after pIpC treatment
• thymus is smaller than in mutant mice with one wild-type Pkn3 allele
|
|
• at 2 weeks after pIpC treatment
|
|
• increase in the number of hematopoietic stem cells in the spleen 2 weeks after pIpC treatment
|
|
• at 2 weeks after pIpC treatment
• thymus is smaller than in mutant mice with one wild-type Pkn3 allele
|
|
• at 2 weeks after pIpC treatment
• thymus is smaller than in mutant mice with one wild-type Pkn3 allele
|
|
• at 2 weeks after pIpC treatment
|
|
• at 2 weeks after pIpC treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• block in erythroblast development resulting in an increase in cells at development stage R2 and a decrease in R4 cell population in spleen and bone marrow 64 weeks post-piPC
|
|
• transplantation of bone marrow from mutants into lethally irradiated CD45.1 recipient mice that were treated with pIPC
results in lower peripheral blood chimerism
• chimerism is lower in LT-HSC to committed myeloid progenitors
• increase in long term repopulating hematopoietic stem cells (LT-HSC) in bone marrow 45 and 64 weeks post-piPC treatment, however, repopulating ability is decrease
• decrease in percentage of granulocyte/monocyte progenitors
|
|
• progressive macrocytic anemia develops following pIPC injection
• anemia is present 4-8 weeks post-injection and is severe by 20 weeks
|
|
• lower percentage of hematopoietic and stem progenitor cells in G1 and a higher percentage in G0 in vitro (24 weeks post-pIPC) as compared to control
|
|
• decrease in percentage of granulocyte/monocyte progenitors in aged mice
|
|
• increase in erythroid precursors in spleens is observed at 64 weeks post-pIPC
• erythroid dysplasia in spleens is observed at 47 weeks post-pIPC
|
|
• total red blood cell number is decreased beginning at 20 weeks post-pIPC injection
• no differences in total white blood cell count, mature white blood cell lineages or platelet counts
|
|
• beginning at 20 weeks post-pIPC injectio
|
|
• macrocytosis is apparent at 20 weeks post-pIPC injection
|
|
• increase in long term repopulating hematopoietic stem cells (LT-HSC) in bone marrow 64 weeks post-piPC treatment, however, repopulating ability is decreased
• no differences in short-term hematopoietic stem cells, multi potent progenitors, common myeloid progenitors, megakaryocytic/erythroid progenitors or colony forming units at 64 weeks post-pIPC
• increase in multi-potent progenitors (MPP) in bone marrow at 12 weeks, but not 45 weeks post-piPC treatment
|
|
• plasma erythropoietin levels are increased and persist for longer than 60 weeks post-pIPC as compared to wild-type
|
|
• transplantation of bone marrow from mutants into lethally irradiated CD45.1 recipient mice that were treated with pIPC
results in lower peripheral blood chimerism
• chimerism is lower in LT-HSC to committed myeloid progenitors
• increase in long term repopulating hematopoietic stem cells (LT-HSC) in bone marrow 45 and 64 weeks post-piPC treatment, however, repopulating ability is decrease
• decrease in percentage of granulocyte/monocyte progenitors
|
|
• 2 mice (18%) die by 64 weeks post piPC no wild-type mice die during this time
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pro-B cell apoptosis is observed in mice after induced cre expression
• viability of immature and mature B cells in the bone marrow is not affected by conditional ablation of Mirn17-92
|
|
• pro-B cells have normal D(H) to J(H) recombination, but V(H) to DJ(H) recombination is less efficient than in wild-type
|
|
• 2-month old mice injected with pI:pC to induce cre expression were found to have reduced numbers of pre-B cells in the bone marrow at 4 weeks after injection
|
|
• pro-B cell apoptosis is observed in mice after induced cre expression
• viability of immature and mature B cells in the bone marrow is not affected by conditional ablation of Mirn17-92
|
|
• pro-B cells have normal D(H) to J(H) recombination, but V(H) to DJ(H) recombination is less efficient than in wild-type
|
|
• 2-month old mice injected with pI:pC to induce cre expression were found to have reduced numbers of pre-B cells in the bone marrow at 4 weeks after injection
|
|
• pro-B cell apoptosis is observed in mice after induced cre expression
• viability of immature and mature B cells in the bone marrow is not affected by conditional ablation of Mirn17-92
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in pIpC-treated mice but not as severe as when Chaf1b alleles are wild-type
|
| N |
• pIpC-treated mice exhibit normal numbers of red blood cells and platelets
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• erythropoietic recovery and spleen size after induction of acute hemolytic stress with 25 mg/kg phenylhydrazine
• no mortality after induction of acute hemolytic stress with high-dose (35 mg/kg) phenylhydrazine
|
| N |
• spleen size after induction of acute hemolytic stress with 25 mg/kg phenylhydrazine
|
| N |
• no mortality after induction of acute hemolytic stress with high-dose (35 mg/kg) phenylhydrazine
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• leukopenia is observed in bone marrow of lethally irritated recipient mice 18 weeks post-transplantation (pIpC injection 4 weeks after transplantation)
• anemia is observed 18 weeks post-bone marrow transplantation (pIpC injection 4 weeks after transplantation)
• hemoglobin is decreased donor bone marrow post-transplantation
• impaired reconstitution of hematopoietic stem/progenitor cells in peripheral blood in competitive bone marrow transplantation assay 14 weeks post-pIpC injection
• decrease in total hematopoietic stem cell (LSK) cell number in bone marrow in competitive bone marrow transplantation assay 14 weeks post-pIpC injection
• decrease in myeloid progenitor total cell number in bone marrow in competitive bone marrow transplantation assay 14 weeks post-pIpC injection
|
|
• bone marrow aplasia is observed 14 weeks post pIpC injection
|
|
• bone marrow aplasia is observed 14 weeks post pIpC injection
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increased in the spleen in mice treated with poly (I:C)
|
|
• ineffective erythropoiesis in bone marrow and spleen in mice treated with poly (I:C)
|
|
• 5 fold increase in splenic erythroid progenitor cells in mice treated with poly (I:C)
• 10 fold increase in primitive erythroid progenitor cells in bone marrow
• increased number of non-viable cells in both spleen and bone marrow
|
|
• 2 fold increase in bone marrow in mice treated with poly (I:C)
|
|
• decreased red blood cell number in mice treated with poly (I:C)
• 50% decrease in mature red blood cell numbers in bone marrow
|
|
• in mice treated with poly (I:C)
|
|
• in mice treated with poly (I:C)
|
|
• in mice treated with poly (I:C)
|
|
• 6 fold decrease in cell number in mice treated with poly (I:C)
• four fold decrease in B cell lineage cells in bone marrow
|
|
• 4 fold decrease in cell number mice treated with poly (I:C)
|
|
• changes in spleen architecture in mice treated with poly (I:C)
|
|
• in mice treated with poly (I:C)
|
|
• 6 fold decrease in cell number in mice treated with poly (I:C)
• four fold decrease in B cell lineage cells in bone marrow
|
|
• 4 fold decrease in cell number mice treated with poly (I:C)
|
|
• changes in spleen architecture in mice treated with poly (I:C)
|
|
• in mice treated with poly (I:C)
|
|
• in mice treated with poly (I:C)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• no mature megakaryocytes are detected in bone marrow
|
|
• lethally irradiated animals transplanted with mutant bone marrow and treated with doxycycline show erythroid progenitor arrest and megakaryocyte differentiation defects in a wild-type bone marrow environment, but do not exhibit anemia or cytopenia; defects are blood cell-autonomous
|
|
• no mature megakaryocytes are detected in bone marrow
|
|
• after induction, no erythroid precursors at or beyond the proerythroblast (monopotent progenitors) stage are detected in the bone marrow
|
|
• numbers of bipotent megakaryocyte and erythrocyte progenitor cells (pre-MegEs) are increased in bone marrow
|
|
• moribund animals have hemoglobin levels of 1-2 g/dl
|
|
• moribund animals have severe thrombocytopenia; some animals have no detectable platelets
|
|
• in some animals
|
|
• pI:pC activation of cre-mediated excision in animals 4-8 weeks of age is lethal in less than 3 weeks
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutant bone marrow transplanted chimeras survive to 250 days after pI-pC treatment
• decreased numbers of CD45.2+eGFP+ DP leukemic cells in the mutant bone marrow transplanted chimeras at 3 and 12 weeks
• CD45.2+eGFP+ DP leukemic cells disappear by 24 weeks
|
|
• decreased B220+ B cell numbers
|
|
• decreased B220+ B cell numbers
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• circulating progenitor cells in the peripheral blood increased 10X in 2 weeks
• levels were also increased in the spleen
• circulating progenitor cell levels remained high for 28 weeks although they moderated over time
• slow recovery of progenitor cell levels in bone marrow
|
|
• moderately reduced B220+ B cells
|
|
• moderately reduced CD4+ T cells
|
|
• significantly increased WBC count in peripheral blood
• mostly due to circulating lymphocytes
|
|
• levels of reticulocytes and erythroid progenitors in general were depressed
• slow recovery from experimental anemia
|
|
• moderately reduced B220+ B cells
|
|
• moderately reduced CD4+ T cells
|
|
• significantly increased WBC count in peripheral blood
• mostly due to circulating lymphocytes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pIpC-treated mice exhibit a slightly decreased in the number of myeloid cells in the bone marrow and peripheral blood compared with control mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit a decrease in the number of granulocyte-monocyte progenitors in the bone marrow compared with control mice
|
|
• slight in the peripheral blood of pIpC-treated mice
|
|
• pIpC-treated mice exhibit reduced LSK cells, long-term hematopoietic stem cells, and short-term hematopoietic stem cells compared with control mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased apoptosis and decreased proliferation of LSK cells compared with control mice
• hematopoietic stem cells from pIpC-treated mice exhibit reduced repopulation capacity compared with cells from control mice
|
|
• pIpC-treated mice exhibit a slightly decreased in the number of myeloid cells in the bone marrow and peripheral blood compared with control mice
|
|
• slight in the peripheral blood of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutant bone marrow transplanted chimeras survive to 26 days after pI-pC treatment
|
|
• three weeks after pI-pC injection, the bone marrow is almost exclusively composed of CD45.2+eGFP+ DP leukemic cells in the mutant bone marrow transplanted chimeras
• infiltration of the spleens by leukemic DP cells
|
|
• severe splenomegaly in mutant bone marrow transplanted chimeras
|
|
• decreased B220+ B cell numbers in mutant bone marrow transplanted chimeras
|
|
• increased WBC counts in mutant bone marrow transplanted chimeras
|
|
• severe splenomegaly in mutant bone marrow transplanted chimeras
|
|
• decreased B220+ B cell numbers in mutant bone marrow transplanted chimeras
|
|
• increased WBC counts in mutant bone marrow transplanted chimeras
|
|
• severe splenomegaly in mutant bone marrow transplanted chimeras
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal numbers of thymocytes, double negative cells, double positive cells and pre-T cell proliferation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• when bone marrow (BM) cells from polyinosinic-polycytidylic acid (pIpC)-treated mutant mice (CD45.2) are transplanted into lethally irradiated (CD45.1) recipient mice, less than 70% of recipients of mutant donor BM cells develop T cell acute lymphoblastic leukemia (T-ALL) with a slower progression and a median survival of 390 days post-transplantation versus 202 days for recipients of wild-type donor BM cells
• after oncogenic Nras activation by pIpC injection, mice develop a chronic myelomonocytic leukemia (CMML)-like disease with a significantly slower progression and a median survival of 173 days post-injection versus 152 days for control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in pIpC-treated mice to a lesser extent than in mice with wild-type Csf3r
|
|
• in pIpC-treated mice to a lesser extent than in mice with wild-type Csf3r
|
|
• in pIpC-treated mice to a lesser extent than in mice with wild-type Csf3r
|
|
• pIpC-treated mice exhibit an increase in Gr1+CD11b+ myeloid cells in the spleen compared with Csf3rtm1Link homozygotes
|
|
• in pIpC-treated mice to a lesser extent than in mice with wild-type Csf3r
|
|
• in pIpC-treated mice to a lesser extent than in mice with wild-type Csf3r
|
|
• in pIpC-treated mice to a lesser extent than in mice with wild-type Csf3r
|
|
• in pIpC-treated mice to a lesser extent than in mice with wild-type Csf3r
|
|
• pIpC-treated mice exhibit an increase in Gr1+CD11b+ myeloid cells in the spleen compared with Csf3rtm1Link homozygotes
|
|
• in pIpC-treated mice to a lesser extent than in mice with wild-type Csf3r
|
|
• in pIpC-treated mice to a lesser extent than in mice with wild-type Csf3r
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice exhibit a mild reduction in red blood cell count and increase in mean red blood cell volume after poly (IC) treatment, indicating macrocytic anemia
|
|
• binucleated erythroid cells and hypo-segmented neutrophils are seen in the bone marrow cells occasionally in poly (IC) treated mice
• megakaryocytes occasionally form clusters in poly (IC) treated mice
• these dysplastic features affect less than 1% of bone marrow cells and are not seen in the peripheral blood
|
|
• mice show a mild reduction in red blood cell count after poly (IC) treatment
• however, platelet numbers are normal, bone marrow cellularity and spleen size are normal after poly (IC) treatment
|
|
• mice show a mild reduction in hematocrit after poly (IC) treatment
|
|
• mice show a mild reduction in hemoglobin concentration after poly (IC) treatment
|
|
• mice show a mild increase in mean corpuscular volume after poly (IC) treatment
|
|
• poly (IC) treated mice show a nearly 50% reduction in numbers of white blood cells, with decreases in all major lineages and the most marked reduction in B220+ B cells
|
|
• the hematopoietic stem cell- and progenitor-enriched LSK cells (Lin-Sca-1+C-Kit+) are decreased in the bone marrow at 36 weeks after poly (IC) treatment; decrease in the LSK cells is due to the reduction of short-term and long-term HSCs (CD48-CD150- and CD48-CD150+, respectively) but not the multipotent progenitors in the bone marrow
• however, no differences are seen in the percentages of Lin- cells and MPs after poly (IC) treatment
|
|
• poly (IC) treated mice show a nearly 50% reduction in numbers of white blood cells, with decreases in all major lineages and the most marked reduction in B220+ B cells
|
| N |
• poly (IC) treated mice exhibit a normal life span
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Increased spleen weight in Ptpn11tm1Ckq/Ptpn11+ Tg(Mx1-cre)1Cgn/0 mice
|
• by 56 weeks due to leukemia in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• around the pro-B stage in pIpC-treated mice
|
|
• all pIpC-treated mice develop myeloproliferative disease (MPD)
• Mac-1+/Gr-1+ mature myeloid cells are increased
• 5 of 27 pIpC-treated mice exhibit accelerated MPD
|
|
• hyperproliferation in the liver and spleen in pIpC-treated mice
|
|
• pIpC-treated mice exhibit decreased common myeloid progenitors, granulocyte macrophage progenitors, and megakaryocyte erythroid progenitors compared with wild-type mice
• however, common lymphoid progenitor numbers are normal
|
|
• in pIpC-treated mice
|
|
• extremely high after 32 weeks with leukemia infiltration in nonhematopoietic organs of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• 3-fold in the bone marrow in pIpC-treated mice
|
|
• in the spleen of pIpC-treated mice
|
|
• hematopoietic stem cells are hyperactivated in pIpC-treated mice
• hematopoietic stem cell quiescent in pIpC-treated mice is decreased 2-fold while the S and G2/M phase were doubled compared to in wild-type mice
• apoptosis of hematopoietic stem cells in pIpC-treated mice is decreased compared to in wild-type mice
|
|
• T cell lymphoblastic leukemia/lymphoma in 9 of 27 pIpC-treated mice
|
|
• after 12 to 32 weeks of chronic myeloproliferative disease in pIpC-treated mice
|
|
• B and T cell lymphoblastic leukemia/lymphoma in pIpC-treated mice
|
|
• acute myeloid leukemia in 6 of 27 pIpC-treated mice
|
|
• B cell lymphoblastic leukemia/lymphoma in 2 of 27 pIpC-treated mice
|
|
• in bone marrow cells and splenocytes from pIpC-treated mice
|
|
• in pIpC-treated mice due to centrosome amplification
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• around the pro-B stage in pIpC-treated mice
|
|
• all pIpC-treated mice develop myeloproliferative disease (MPD)
• Mac-1+/Gr-1+ mature myeloid cells are increased
• 5 of 27 pIpC-treated mice exhibit accelerated MPD
|
|
• extremely high after 32 weeks with leukemia infiltration in nonhematopoietic organs of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• T cell lymphoblastic leukemia/lymphoma in 9 of 27 pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• splenocytes and bone marrow cells from pIpC-treated mice exhibit increased colony-forming units compared with control mice
|
|
• non-cell-autonomous in pIpC-treated mice
|
|
• at an early stage in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit an increase in Gr1+CD11b+ myeloid cells in the spleen compared with control mice
• however, no difference was observed in the bone marrow
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit myeloid infiltration in the spleen unlike in control mice
|
|
• severe in pIpC-treated mice with expansion of red pulp
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• metatarsal bone marrow in pIpC-treated mice is filled with hematopoietic cells instead of being replaced with fat cells as in control mice
|
|
• non-cell-autonomous in pIpC-treated mice
|
|
• non-cell-autonomous in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• at an early stage in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit an increase in Gr1+CD11b+ myeloid cells in the spleen compared with control mice
• however, no difference was observed in the bone marrow
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit myeloid infiltration in the spleen unlike in control mice
|
|
• severe in pIpC-treated mice with expansion of red pulp
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• severe in pIpC-treated mice with expansion of red pulp
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• fewer IL9+ cells in IFN-alpha-treated mice following differentiation towards Th9 lineage
|
|
• fewer IL9+ cells in IFN-alpha-treated mice following differentiation towards Th9 lineage
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• all mice die within 45 weeks after receiving pIpC injections
|
|
• following pIpC injections mice develop splenomegaly
|
|
• following pIpC injections cultured bone marrow megakaryocyte-erythrocyte progenitor cells produce fewer erythrocyte colony-forming unit colonies and more, larger erythroid burst-forming unit colonies
• the myeloproliferative disorder seen after pIpC injections does not develop in irradiated mice engrafted with cells from diseased mice
|
|
• following pIpC injections common myeloid progenitor cell numbers are reduced in the bone marrow
|
|
• following pIpC injections cultured erythroid progenitors produce fewer erythrocyte colony-forming unit colonies
|
|
• following pIpC injections both bone marrow and spleen cells form increased numbers of cytokine independent colonies that are primarily macrophage colony forming units and granulocyte colony forming units
|
|
• following pIpC injections mice develop marked extramedullary hematopoiesis with an increase in the numbers of long term and short term hematopoietic stem cells and granulocyte-monocyte progenitor cells following pIpC injections
|
|
• following pIpC injections increased numbers of immature predominantly granulocytic cells are found in the bone marrow
|
|
• following pIpC injections total bone marrow cellularity is decreased
|
|
• following pIpC injections granulocyte-monocyte progenitor cell numbers are reduced in the bone marrow
|
|
• following pIpC injections mice develop progressive leukocytosis
|
|
• following pIpC injections mice develop progressive granulocytosis
|
|
• following pIpC injections mice develop progressive monocytosis
|
|
• following pIpC injections the sizes of the Lin-Sca1+cKit+ (LSK) and Lin-Sca1-cKit+ (LK) compartments in the bone marrow are reduced
• following pIpC injections fewer cells in the LSK compartment are quiescent and these cells are hypersensitive to stem cell factor
• following pIpC injections the number of long term hematopoietic stem cells is reduced
|
|
• following pIpC injections infiltration of mature myeloid cells into the red pulp is seen
|
|
• following pIpC injections the ratio of Mac1+Gr1+ cells is increased 9 to 10 fold, the ratio of erythroid progenitors is increased 6 to 7 fold, and the relative number of T cells is decreased
|
|
• following pIpC injections periportal cuffing of liver sinusoids with infiltrating granulocytes is seen
|
|
• following pIpC injections mice develop hepatomegaly
|
|
• following pIpC injections mice develop splenomegaly
|
|
• following pIpC injections both bone marrow and spleen cells form increased numbers of cytokine independent colonies that are primarily macrophage colony forming units and granulocyte colony forming units
|
|
• following pIpC injections mice develop progressive leukocytosis
|
|
• following pIpC injections mice develop progressive granulocytosis
|
|
• following pIpC injections mice develop progressive monocytosis
|
|
• following pIpC injections infiltration of mature myeloid cells into the red pulp is seen
|
|
• following pIpC injections the ratio of Mac1+Gr1+ cells is increased 9 to 10 fold, the ratio of erythroid progenitors is increased 6 to 7 fold, and the relative number of T cells is decreased
|
|
• following pIpC injections periportal cuffing of liver sinusoids with infiltrating granulocytes is seen
|
|
• following pIpC injections mice develop hepatomegaly
|
|
• following pIpC injections mice develop splenomegaly
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| juvenile myelomonocytic leukemia | DOID:0050458 |
OMIM:607785 |
J:148430 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• defects in the stem cell compartment are identical to mice heterozygous for Pbx1tm1Mlc and
Pbx1tm3.1Mlc and carrying Tg(Tek-cre)1Ywa
|
|
• reduction in the number of common lymphoid progenitor cells
|
|
• assays indicate that long term hematopoietic stem cells are impaired in self renewal
|
|
• significant reduction in the number of long term hematopoietic stem cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• pIpC-treated bone marrow cells fails to contribute to hematopoiesis in a competitively reconstituted bone marrow recipient unlike wild-type cells
|
|
|
• following pIpC treatment, mice exhibit a reduction in lymphoid progenitor cells compared with wild-type mice
|
|
|
• pIpC induction, lymphocyte are depleted and fail to regenerate unlike in similarly treated wild-type mice
|
|
|
• 2 weeks after pIpC induction, the number of hematopoietic stem cell-containing LSK populations is decreased compared to in similarly treated wild-type mice
• following pIpC treatment, mice exhibit a reduction in hematopoietic stem cells, specifically self-renewing long-term and short-term hematopoietic stem cells and lymphoid progenitor cells, compared with wild-type mice
• however, proliferation of pIpC-treated erythroid-myeloid progenitor cells is normal
|
|
|
• following pIpC treatment, hematopoietic stem cell apoptosis is increased compared to in similarly treated wild-type mice
• following pIpC treatment, maintenance of adult hematopoietic cells is abolished compared to in similarly treated wild-type mice
|
|
|
• pIpC induction, lymphocyte are depleted and fail to regenerate unlike in similarly treated wild-type mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 2 weeks after the final pIpC injection liver size is increased about 2-fold
• gradual increase in hypertrophic hepatocytes with grainy cytoplasm following pIpC injections
|
|
• 2 weeks after the final pIpC injection liver weight is increased about 2-fold
|
|
• dramatic depletion of glycogen in hepatocytes after pIpC injections
|
|
• gradual increase in hypertrophic hepatocytes with grainy cytoplasm following pIpC injections
|
|
• after pIpC injections
|
|
• dramatic depletion of glycogen in hepatocytes after pIpC injections
|
|
• 2 weeks after the final pIpC injection liver size is increased about 2-fold
• gradual increase in hypertrophic hepatocytes with grainy cytoplasm following pIpC injections
|
|
• 2 weeks after the final pIpC injection liver weight is increased about 2-fold
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increased cell death in GMPs and their progeny during culture with GM-CSF up to the fifth generation
|
|
• no elevation of neutrophils 18 days after induced myelosuppression by 5-FU injection
• severely impaired GM-CSF-induced increase of peripheral blood neutrophils
|
|
• longer generation times in every generation (F1 through F4) during culture with GM-CSF compared with control cells
|
|
• decreased absolute number of bone marrow mononuclear cells (BMMNCs) from both femora and tibiae per mouse
• decreased absolute number of granulocyte-macrophage progenitors (GMPs) from both femora and tibiae per mouse
• impaired colony formation of GMPs
• reduced numbers of mutant colonies by more than 50% in the presence of GM-CSF
• the average cell number of a mutant GMP-derived colony is only 11% of that from control GMPs
• normal percentage of GMPs in BMMNCs
|
|
• no elevation of neutrophils 18 days after induced myelosuppression by 5-FU injection
• severely impaired GM-CSF-induced increase of peripheral blood neutrophils
|
|
• decreased white blood cell counts
|
|
• decreased absolute number of peripheral neutrophils by 50% in homeostasis 3 weeks after PolyIC injection
|
|
• decreased lymphocytes counts (70% decrease)
|
|
• decreased monocytes counts (44% decrease)
|
|
• only 65% of mutant bone marrow neutrophils, compare with virtually all cells from control animals survive for 36 hours in the presence of GM-CSF
|
|
• decreased absolute number of bone marrow mononuclear cells (BMMNCs) from both femora and tibiae per mouse
• decreased absolute number of granulocyte-macrophage progenitors (GMPs) from both femora and tibiae per mouse
• impaired colony formation of GMPs
• reduced numbers of mutant colonies by more than 50% in the presence of GM-CSF
• the average cell number of a mutant GMP-derived colony is only 11% of that from control GMPs
• normal percentage of GMPs in BMMNCs
|
|
• no elevation of neutrophils 18 days after induced myelosuppression by 5-FU injection
• severely impaired GM-CSF-induced increase of peripheral blood neutrophils
|
|
• decreased white blood cell counts
|
|
• decreased absolute number of peripheral neutrophils by 50% in homeostasis 3 weeks after PolyIC injection
|
|
• decreased lymphocytes counts (70% decrease)
|
|
• decreased monocytes counts (44% decrease)
|
|
• only 65% of mutant bone marrow neutrophils, compare with virtually all cells from control animals survive for 36 hours in the presence of GM-CSF
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• there is a 14-fold decrease in mature megakaryocytes and a 2.3 fold reduction in immature megakaryocytes after treatment
|
|
• myeloid progenitors increase 3- to 9-fold over littermate controls after polyinosinic-polycytidylic injection (pIpC)
• there is a predominant population of abnormal myeloid progenitors
• abnormal progenitors have myeloid-erythroid progentior immunophenotype
• in culture, 1.5- to 2.5 fold increase is observed in erythroid and myeloid colonies generated from bone marrow
• number of smaller colonies compared to control is significantly greater
• proliferative capacity of abnormal myeloid precursors is reduced
|
|
• platelet counts are reduced 50% at 2 weeks after injection with pIpC
|
|
• numbers of hematopoietic stem cells increases 2-to 3-fold over littermate controls
|
|
• infiltration of leukemic cells in spleen
|
|
• mice with acute myeloid leukemia have splenomegaly
|
|
• infiltration of leukemic cells in liver
|
|
• myeloid progenitors increase 3- to 9-fold over littermate controls after polyinosinic-polycytidylic injection (pIpC)
• there is a predominant population of abnormal myeloid progenitors
• abnormal progenitors have myeloid-erythroid progentior immunophenotype
• in culture, 1.5- to 2.5 fold increase is observed in erythroid and myeloid colonies generated from bone marrow
• number of smaller colonies compared to control is significantly greater
• proliferative capacity of abnormal myeloid precursors is reduced
|
|
• infiltration of leukemic cells in spleen
|
|
• mice with acute myeloid leukemia have splenomegaly
|
|
• there is a 14-fold decrease in mature megakaryocytes and a 2.3 fold reduction in immature megakaryocytes after treatment
|
|
• mice with acute myeloid leukemia have splenomegaly
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutants treated with poly I:C rarely survive beyond 4-5 weeks of age due to granulocytopenia and sepsis
|
|
• a dramatic loss of Gr-1+ Mac-1+ neutrophils/monocytes is seen in the bone marrow, spleen, and peripheral blood, however T and B cell numbers are normal
|
|
• after poly I:C treatment myelocytes, neutrophils, monocytes, and eosinophils are rarely seen in the bone marrow and the number of immature myeloblasts is increased 32%
• in vitro common myeloid progenitor cells fail to form any mature granulocyte-macrophage, macrophage, or granulocytic colonies
|
|
• injection of poly I:C at 2 days after birth resulted in absence of mature granulocytes, however mutants do not develop anemia, thrombocytopenia, or leukemia
|
|
• a dramatic loss of Gr-1+ Mac-1+ neutrophils/monocytes is seen in the bone marrow, spleen, and peripheral blood, however T and B cell numbers are normal
|
|
• after poly I:C treatment myelocytes, neutrophils, monocytes, and eosinophils are rarely seen in the bone marrow and the number of immature myeloblasts is increased 32%
• in vitro common myeloid progenitor cells fail to form any mature granulocyte-macrophage, macrophage, or granulocytic colonies
|
|
• injection of poly I:C at 2 days after birth resulted in absence of mature granulocytes, however mutants do not develop anemia, thrombocytopenia, or leukemia
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• induced mice exhibit impaired triglyceride secretion from the liver, and significantly decreased de novo lipid (fatty acids and sterols) synthesis in the liver
|
|
• at 3 weeks after cre induction with poly(I:C), plasma triglyceride levels are lower than in wild-type
|
|
• at 3 weeks after cre induction with poly(I:C), an almost complete absence of LDL-associated cholesterol in primary hepatocytes
|
|
• at 3 weeks after cre induction with poly(I:C), free fatty acid levels in isolated hepatocytes are reduced compared to wild-type controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• decreased absolute number of bone marrow mononuclear cells (BMMNCs) from both femora and tibiae per mouse
• decreased absolute number of granulocyte-macrophage progenitors (GMPs) from both femora and tibiae per mouse
• normal percentage of GMPs in BMMNCs
• impaired colony formation of GMPs
• reduced numbers of mutant colonies by more than 50% in the presence of GM-CSF
• the average cell number of a mutant GMP-derived colony is only 11% of that from control GMPs
|
|
• no elevation of neutrophils 18 days after induced myelosuppression by 5-FU injection
• severely impaired GM-CSF-induced increase of peripheral blood neutrophils
|
|
• decreased white blood cell counts
|
|
• decreased absolute number of peripheral neutrophils by 50% in homeostasis 3 weeks after PolyIC injection
|
|
• decreased lymphocytes counts (70% decrease)
|
|
• decreased monocytes counts (44% decrease)
|
|
• only 65% of mutant bone marrow neutrophils, compare with virtually all cells from control animals survive for 36 hours in the presence of GM-CSF
|
|
• decreased absolute number of bone marrow mononuclear cells (BMMNCs) from both femora and tibiae per mouse
• decreased absolute number of granulocyte-macrophage progenitors (GMPs) from both femora and tibiae per mouse
• normal percentage of GMPs in BMMNCs
• impaired colony formation of GMPs
• reduced numbers of mutant colonies by more than 50% in the presence of GM-CSF
• the average cell number of a mutant GMP-derived colony is only 11% of that from control GMPs
|
|
• no elevation of neutrophils 18 days after induced myelosuppression by 5-FU injection
• severely impaired GM-CSF-induced increase of peripheral blood neutrophils
|
|
• decreased white blood cell counts
|
|
• decreased absolute number of peripheral neutrophils by 50% in homeostasis 3 weeks after PolyIC injection
|
|
• decreased lymphocytes counts (70% decrease)
|
|
• decreased monocytes counts (44% decrease)
|
|
• only 65% of mutant bone marrow neutrophils, compare with virtually all cells from control animals survive for 36 hours in the presence of GM-CSF
|
|
• increased cell death in GMPs and their progeny during culture with GM-CSF up to the fifth generation
|
|
• no elevation of neutrophils 18 days after induced myelosuppression by 5-FU injection
• severely impaired GM-CSF-induced increase of peripheral blood neutrophils
|
|
• longer generation times in every generation (F1 through F4) during culture with GM-CSF compared with control cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• induced mice start to show significant mortality starting at ~22 weeks with ~90% mortality by 75 weeks of age
|
|
|
• by 19-30 weeks, after cre induction, mice develop aggressive CD8+ CD4+ thymic lymphomas that spread to the spleen, lymph nodes and liver
• wild-type mice and all other conditional genotypes examined here do not show any lymphomas up to 100 weeks of age
|
|
|
• mice develop an age-progressive hamarotomatous phenotype with cre expression
|
|
|
• mice show widespread development of hemangiomas, most exaggerated in uterus and visible by 6-8 weeks
• lesions (usually benign) progress greatly by 30-40 weeks, with affected animals showing massive hemangiomas with intraluminal blood and thrombi in skeletal muscle, abdominal wall, liver, adrenal glands, bone marrow, omentum, lymph nodes, and skin
|
|
|
• in ~9% of mice, lesions progress to lethal angiosarcomas
|
|
|
• by 19-30 weeks, after cre induction, mice develop aggressive CD8+ CD4+ thymic lymphomas that spread to the spleen, lymph nodes and liver
• wild-type mice and all other conditional genotypes examined here do not show any lymphomas up to 100 weeks of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• development of hemangiomas leads to premature death starting to significant levels at ~50 weeks of age with induced cre expression
|
|
|
• mice develop an age-progressive hamarotomatous phenotype with cre expression
|
|
|
• females display mild hemangiomas, most exaggerated in the uterus and occasionally other tissues by 6-8 weeks after induction of cre expression with poly(I:C)
|
|
|
• discrete liver hemangiomas and occasionally angiosarcomas are observed in aged mice (5/7 in mice that died at 58-86 weeks and 2/2 examined at 96-98 weeks)
|
|
|
• in ~9% of mice, lesions progress to lethal angiosarcomas
|
|
|
• discrete liver hemangiomas and occasionally angiosarcomas are observed in aged mice (5/7 in mice that died at 58-86 weeks and 2/2 examined at 96-98 weeks)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• most mice die within 2 to 3 weeks of pIpC treatment
|
| N |
• hematopoietic stem cells in pIpC-treated mice exhibit normal apoptosis rates
|
|
• decreased bone marrow myeloid and lymphoid progenitors in pIpC-treated mice
|
|
• decreased bone marrow myeloid and lymphoid progenitors in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• increased hematopoietic stem cells and multipotent progenitors in the bone marrow of pIpC-treated mice
|
|
• hematopoietic stem cells (HCS) from pIpC-treated mice fail to differentiate in colony forming assays
• cell-autonomous defect in differentiation and blocked repopulating capabilities in HCS from pIpC-treated mice
• HSCs from pIpC-treated mice accumulate at the G1 phase and exhibit enhanced entry of quiescence
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in the bone marrow of pIpC-treated mice
|
|
• in the bone marrow of pIpC-treated mice
|
|
• in the bone marrow of pIpC-treated mice
|
|
• in the bone marrow of pIpC-treated mice
|
|
• in the bone marrow of pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• progressive after pIpC treatment
|
|
• pIpC-treated mice exhibit bone marrow failure that is hemopoeitic-specific and cell-autonomous
|
|
• in the bone marrow of pIpC-treated mice
|
|
• progressive after pIpC treatment
|
|
• in the bone marrow of pIpC-treated mice
|
|
• in the bone marrow and spleen of pIpC-treated mice
|
|
• in the bone marrow of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in the bone marrow of pIpC-treated mice at the time of death
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in the blood and bone marrow of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• B cell and B-type progenitors in the bone marrow of pIpC-treated mice
|
|
• in the bone marrow and spleen of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• virtual absence of short and long term hematopoietic stem cells (HSCs) in the bone marrow of pIpC-treated mice
• progressive 11-fold decrease as early as 12 days after pIpC treatment
• decreased LT-HSCs in the spleens of pIpC-treated mice
|
|
• reduced proliferation of long term HSCs, myeloid progenitors, and total bone marrow cells in pIpC-treated mice
• increased apoptosis of myeloid progenitors in pIpC-treated mice
|
|
• 9-fold decrease in hematopoietic stem cell mobilization to the spleen in pIpC-treated mice
|
|
• in long term HSCs of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in the blood and bone marrow of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• B cell and B-type progenitors in the bone marrow of pIpC-treated mice
|
|
• in the bone marrow and spleen of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in long term HSCs of pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Inflammation in the lung and liver and destruction of spleen architecture of Tnfaip3tm1Homy/Tnfaip3tm1Homy Tg(Mx1-cre)1Cgn/? mice
|
• spontaneous emaciation and cachexia without stimulation with polyinosinic:polycytidylic acid (pIpC)
|
|
• most mice die within six months of birth
|
| N |
• no significant differences in WBC and platelets between homozygotes and controls at 3 and 6 months
|
|
• proliferation of myeloid cells
|
|
• reduced B lymphoid cell numbers in peripheral blood
|
|
• destruction of spleen architecture due to proliferation of white blood cells of myeloid origin
|
|
• proliferation of myeloid cells
|
|
• reduced B lymphoid cell numbers in peripheral blood
|
|
• destruction of spleen architecture due to proliferation of white blood cells of myeloid origin
|
|
• significantly increased levels of GM-CSF
|
|
• significantly increased
|
|
• elevated
|
|
• elevated
|
|
• significantly increased TNF-alpha levels
|
|
• swelling of lymph nodes
|
|
• infiltration with hematopoietic cells
|
|
• infiltration of lungs with hematopoietic cells
|
|
• infiltration with hematopoietic cells
|
|
• infiltration of lungs with hematopoietic cells
|
|
• significantly increased levels of GM-CSF
|
|
• significantly increased
|
|
• elevated
|
|
• elevated
|
|
• significantly increased TNF-alpha levels
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• induction of cre expression at 6 weeks of age leads to loss of the T cell receptor complex (TCR)
• by 10 days after induction of cre, all T cells have lost normal expression of the TCR
• sensitive techniques reveal a very low level of TCR complex detectable on all T cells 10, 37 and 49 days after cre induction
|
|
• the half-life decay of the CD4+ T cells after cre induction is 46 days compared to 78 days in controls
|
|
• the half-life decay of the CD8+ T cells after cre induction is 16 days compared to 162 days in controls
|
|
• after cre induction and loss of CD4 T cells, memory CD4 T cell numbers expand and fill the compartment
|
|
• induction of cre expression at 6 weeks of age leads to loss of the T cell receptor complex (TCR)
• by 10 days after induction of cre, all T cells have lost normal expression of the TCR
• sensitive techniques reveal a very low level of TCR complex detectable on all T cells 10, 37 and 49 days after cre induction
|
|
• the half-life decay of the CD4+ T cells after cre induction is 46 days compared to 78 days in controls
|
|
• the half-life decay of the CD8+ T cells after cre induction is 16 days compared to 162 days in controls
|
|
• after cre induction and loss of CD4 T cells, memory CD4 T cell numbers expand and fill the compartment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in 10% of mice following pIpC administration
|
|
• in 10% of mice following pIpC administration
|
|
• at 6 and 26 weeks following pIpC administration, the number of pro-erythrocytes and terminally differentiated erythroblasts is increased compared to in wild-type mice
|
|
• following pIpC administration,10% of mice exhibit increase in Ter119+ erythroid cells in bone marrow (BM), CD71+Ter119+ erythroid cells in the spleen, and Mac1+Gr1+ cells in BM and spleen compared with wild-type mice
• following pIpC administration, one mouse exhibited granulocytic hyperplasia, patchy accumulation of immature cells, reduction of erythroid and megakaryocytic cells, development of collagen fibrosis, decreased Ter119+ erythroid cells in BM, increased CD71+Ter119+ erythroid cells in the spleen, and increased Mac1+Gr1+ cells in BM and spleen compared with wild-type mice
|
|
• 26 weeks following pIpC administration, the number of Gr+Mac1+ cells is modestly increased compared to in wild-type mice
• 10 weeks after pIpC treatment, bone marrow cells exposed to thrombopoietin (TPO) exhibit increased number of ploidy CD41+ cells compared with similarly treated wild-type cells
|
|
• 6 weeks, but not 26 weeks, after pIpC treatment, mice exhibit increased bone marrow-derived colony-forming units-granulocyte, colony-forming units-macrophage, and colony forming units granulocyte-macrophage (CFU-GM) compared with wild-type mice
• however, no TPO-independent megakaryocyte colonies are observed
|
|
• at 6 and 26 weeks following pIpC administration, mice exhibit megakaryocytic hyperplasia with large and hyperlobated forms unlike in wild-type mice
|
|
• modestly at 6 weeks after pIpC treatment in the presence or absence of erythropoietin (EPO)
• significant at 26 weeks after pIpC and EPO treatment with an increase in EPO-independent BFU-E at 26 weeks
|
|
• in 10% of mice following pIpC administration
|
|
• in 10% of mice following pIpC administration
|
|
• following pIpC administration
|
|
• following pIpC administration
|
|
• in one mouse following pIpC administration
|
|
• following pIpC administration
|
|
• after pIpC treatment, mice exhibit reduced numbers of LSK cells compared with wild-type mice
|
|
• after pIpC treatment, LSK cells exhibit increased DNA damage, reduced cell cycling, and reduced apoptosis compared with wild-type mice
• in transplantation assays, hematopoietic stem cells from pIpC treated mice exhibits impaired long-term repopulation compared with wild-type cells
|
|
• in 10% of mice following pIpC administration
|
|
• in one mouse following pIpC administration
|
|
• following pIpC administration
|
|
• following pIpC administration,10% of mice exhibit bone marrow fibrosis unlike wild-type mice
|
|
• 26 weeks following pIpC administration, the number of Gr+Mac1+ cells is modestly increased compared to in wild-type mice
• 10 weeks after pIpC treatment, bone marrow cells exposed to thrombopoietin (TPO) exhibit increased number of ploidy CD41+ cells compared with similarly treated wild-type cells
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| essential thrombocythemia | DOID:2224 |
OMIM:187950 OMIM:601977 OMIM:614521 |
J:164539 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following partial hepatectomy, proliferation of pIpC-treated hepatocyte is decreased compared to in wild-type mice due to accumulation of DNA damage
• however, a subset of hepatocytes resolve their DNA damage and divide
|
|
• while liver regeneration following partial hepatectomy is normal, pIpC-treated hepatocytes exhibit an increase in DNA damage compared to wild-type cells
• however, a subset of hepatocytes resolve their DNA damage and divide
|
|
• following partial hepatectomy, pIpC-treated livers exhibit reduced cellularity and endoreduplication compared to in similarly-treated wild-type mice
|
|
• the only viable bone marrow left after treatment with pIpC fails to exhibit recombination
|
|
• following partial hepatectomy, proliferation of pIpC-treated hepatocyte is decreased compared to in wild-type mice due to accumulation of DNA damage
• however, a subset of hepatocytes resolve their DNA damage and divide
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pIpC-treated mice die within 30 days
|
|
• in pIpC-treated mice (including CFU-G, CFU-M, CFU-GM, and CFU-GEMM)
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit a reduction of common myeloid progenitors (CMP), granulocyte-macrophage progenitors (GMP), and megakaryocyte-erythroid progenitors (MEP) compared with similarly treated control mice
|
|
• in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• post-piPC treatment
|
|
• block in erythroblast development results in an increase in cells at development stage R2 and a decrease in R4 population in spleen by 12 weeks post-piPC
|
|
• transplantation of bone marrow from mutants into lethally irradiated CD45.1 recipient mice that were treated with pIPC results in increasing (46.5% to 90%) donor chimerism beginning at 16 weeks post transplantation as compared to mice carrying only the Sf3b1tm1.1Mdf allele and wild-type
|
|
• progressive macrocytic anemia 45 weeks post pIPC treatment
|
|
• spleens contain dysplastic megakaryocytes 45 weeks post-piPC treatment
|
|
• spleens contain dysplastic erythroid progenitors 45 weeks post-piPC treatment
|
|
• observed at 45 weeks post-pIPC injection
• phenotype is increased in severity as compared to mice carrying only the Sf3b1tm1.1Mdf allele
|
|
• post-pIPC treatment
|
|
• increased percentage of granulocytes in peripheral blood and bone marrow at 45 weeks post-pIPC
|
|
• decrease in percentage of B cells in the spleen and bone marrow 45 weeks post-pIPC
|
|
• increase in long term repopulating hematopoietic stem cells (LT-HSC) at 12 and 45 weeks as compared to wild-type
• increase in multi-potent progenitors (MPP) in bone marrow 12 weeks post-piPC treatment
|
|
• post-piPC treatment
|
|
• transplantation of bone marrow from mutants into lethally irradiated CD45.1 recipient mice that were treated with pIPC results in increasing (46.5% to 90%) donor chimerism beginning at 16 weeks post transplantation as compared to mice carrying only the Sf3b1tm1.1Mdf allele and wild-type
|
|
• increased percentage of granulocytes in peripheral blood and bone marrow at 45 weeks post-pIPC
|
|
• decrease in percentage of B cells in the spleen and bone marrow 45 weeks post-pIPC
|
|
• post-piPC treatment
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| myelodysplastic syndrome | DOID:0050908 |
OMIM:614286 |
J:234976 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• defective ligand scavenging in pIpC treated mice
• decreased migration in sterile peritonitis in pIpC-treated mice
|
|
• in pIpC treated mice
|
|
• defective ligand scavenging in pIpC treated mice
• decreased migration in sterile peritonitis in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 6 month old mice show dysplasia of circulating myeloid cells following pI:pC treatment
|
|
• mice treated with polyinosinicpolycytidylic acid (pI:pC) show infiltration of liver with hematopoietic cells, indicating extramedullary hematopoiesis
|
|
• 1.4- to 2-fold increase in CD71+/Ter119- erythoroid precursor cells in the bone marrow and spleen following pI:pC treatment, indicating impaired erythroid differentiation
|
|
• hemoglobin is reduced at between 6 and 12 months of age after pI:pC treatment, but not in younger mice
|
|
• following pI:pC treatment, mice show frequent circulating nucleated red cells at 6 months of age
|
|
• following pI:pC treatment, mice develop progressive leukopenia that is most apparent at 6-12 months of age
• leukopenia is predominately as a result of decreased B220+ mature B cells, CD11b+Gr1+ neutrophils, and CD11b+Gr1- monocytes
|
|
• decrease in CD11b+Gr1+ neutrophils following pI:pC treatment
|
|
• mice show a decrease in B220+ mature B cells following pI:pC treatment
|
|
• decrease in CD11b+Gr1- monocytes following pI:pC treatment
|
|
• 6 month old mice show dysplasia of circulating myeloid cells following pI:pC treatment
|
|
• following pI:pC treatment, mice develop progressive leukopenia that is most apparent at 6-12 months of age
• leukopenia is predominately as a result of decreased B220+ mature B cells, CD11b+Gr1+ neutrophils, and CD11b+Gr1- monocytes
|
|
• decrease in CD11b+Gr1+ neutrophils following pI:pC treatment
|
|
• mice show a decrease in B220+ mature B cells following pI:pC treatment
|
|
• decrease in CD11b+Gr1- monocytes following pI:pC treatment
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| myelodysplastic syndrome | DOID:0050908 |
OMIM:614286 |
J:208092 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• few inclusions form immediately following injection of inosinic acid-polycytidylic acid (pIpC) but large ubiquitin-positive inclusions are present 16 days post-injection
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• post-pIPC treatment
|
|
• block in erythroblast development resulting in an increase at development stage R2 and a decrease in R4 population in spleen at 45 weeks post-piPC
|
|
• transplantation of bone marrow from mutants into lethally irradiated CD45.1 recipient mice that were treated with post-pIPC results in 100% donor chimerism by 24 weeks as compared to approximately 25% in wild-type
|
|
• increased percentage of granulocytes in peripheral blood and bone marrow at 45 weeks post-pIPC
|
|
• decrease in percentage of B cells in the spleen and bone marrow 45 weeks post-pIPC
|
|
• increase in long term repopulating hematopoietic stem cells (LT-HSC) in bone marrow 45 weeks post-piPC treatment
• increase in multi-potent progenitors (MPP) in bone marrow 12 weeks post-piPC treatment
• increase in short term repopulating hematopoietic stem cells (ST-HSC) in bone marrow 45 weeks post-piPC treatment
|
|
• in transplantation experiments, pIpC-treated hematopoietic stem cells exhibit increased self-renewal compared with control cells
|
|
• post-pIPC treatment
|
|
• transplantation of bone marrow from mutants into lethally irradiated CD45.1 recipient mice that were treated with post-pIPC results in 100% donor chimerism by 24 weeks as compared to approximately 25% in wild-type
|
|
• increased percentage of granulocytes in peripheral blood and bone marrow at 45 weeks post-pIPC
|
|
• decrease in percentage of B cells in the spleen and bone marrow 45 weeks post-pIPC
|
|
• 17.7% of mice treated with polyinosinicpolycytidylic acid (pIpC) at 4 weeks of life die by 50 weeks of age
|
|
• post-pIPC treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 40% of mice treated with polyinosinicpolycytidylic acid (pI:pC) at 4 weeks of life die by 50 weeks of age
|
|
• transplantation of bone marrow from mutants into lethally irradiated CD45.1 recipient mice that were treated with pI:pC results in a myelodysplastic syndrome and mice exhibit lower white blood cell counts and hematocrit, presence of dysplastic erythroid precursors, dysplastic myloid cells, and increased extramedullary hematopoiesis
|
|
• transplantation of bone marrow from mutants into lethally irradiated CD45.1 recipient mice that were treated with pI:pC results in a myelodysplastic syndrome and mice exhibit lower white blood cell counts and hematocrit, presence of dysplastic erythroid precursors, dysplastic myloid cells, and increased extramedullary hematopoiesis
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die within 10 days following induction with pIpC
• cells induced with pIpC, when transplanted into irradiated wild-type mice, causes a lethal failure of hematopoiesis
|
|
• presumably due to spontaneous production of interferon in induced and un-induced mice
|
|
• following induction with pIpC, blood counts of mature hematopoietic cells is reduced
• cells induced with pIpC, when transplanted into irradiated wild-type mice, causes a lethal failure of hematopoiesis
|
|
• 4 days following induction with pIpC, bone marrow cellularity is reduced 10-fold due to 4.5-fold increase in apoptosis and decreased proliferation
|
|
• in the one mouse that survived 10 days following induction with pIpC
|
|
• in the one mouse that survived 10 days following induction with pIpC
|
|
• following induction with pIpC, hematopoietic progenitor cells are not detected
|
|
• following induction with pIpC, the neutrophil count is reduced to near zero by day 4
|
|
• following induction with pIpC, lymphocyte counts decrease to a greater extent than in similarly treated mice without the cre transgene and do not recover
|
|
• following induction with pIpC, monocyte counts decrease to a greater extent than in similarly treated mice without the cre transgene and do not recover
|
|
• irregular following induction with pIpC
|
|
• following induction with pIpC, red pulp size is reduced with a marked loss of hematopoietic cells
|
|
• following induction with pIpC
|
|
• following induction with pIpC, spleen cellularity is reduced 2-fold
|
|
• following induction with pIpC, white pulp is moderately reduced with increased apoptosis of lymphocytes compared to in mice without the cre transgene
|
|
• following induction with pIpC, mice exhibit an increase in the number of apoptotic enterocytes at the base and along the crypts
|
|
• following induction with pIpC, enterocytes are hyperchromatic with enlarged nuclei and loss of polarity
• following induction with pIpC, villus enterocytes are swollen with vacuolated cytoplasm and small pycnotic nuclei
|
|
• following induction with pIpC, scattered crypts are diluted with necrotic cellular debris and lined by flattened epithelial cells
|
|
• following induction with pIpC, mice exhibit villus atrophy with an increase in the number of apoptotic enterocytes at the base and along the crypts
|
|
• presumably due to spontaneous production of interferon in induced and un-induced mice
|
|
• following induction with pIpC, the neutrophil count is reduced to near zero by day 4
|
|
• following induction with pIpC, lymphocyte counts decrease to a greater extent than in similarly treated mice without the cre transgene and do not recover
|
|
• following induction with pIpC, monocyte counts decrease to a greater extent than in similarly treated mice without the cre transgene and do not recover
|
|
• irregular following induction with pIpC
|
|
• following induction with pIpC, red pulp size is reduced with a marked loss of hematopoietic cells
|
|
• following induction with pIpC
|
|
• following induction with pIpC, spleen cellularity is reduced 2-fold
|
|
• following induction with pIpC, white pulp is moderately reduced with increased apoptosis of lymphocytes compared to in mice without the cre transgene
|
|
• following induction with pIpC, scattered crypts are diluted with necrotic cellular debris and lined by flattened epithelial cells
|
|
• presumably due to spontaneous production of interferon in induced and un-induced mice
|
|
• following induction with pIpC, mice exhibit an increase in the number of apoptotic enterocytes at the base and along the crypts
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die within 10 days following induction with pIpC
• cells induced with pIpC, when transplanted into irradiated wild-type mice, causes a lethal failure of hematopoiesis
|
|
• following induction with pIpC, mice exhibit an increase in the number of apoptotic enterocytes at the base and along the crypts
|
|
• following induction with pIpC, enterocytes are hyperchromatic with enlarged nuclei and loss of polarity
• following induction with pIpC, villus enterocytes are swollen with vacuolated cytoplasm and small pycnotic nuclei
|
|
• following induction with pIpC, scattered crypts are diluted with necrotic cellular debris and lined by flattened epithelial cells
|
|
• following induction with pIpC, mice exhibit villus atrophy with an increase in the number of apoptotic enterocytes at the base and along the crypts
|
|
• following induction with pIpC, scattered crypts are diluted with necrotic cellular debris and lined by flattened epithelial cells
|
|
• presumably due to spontaneous production of interferon in induced and un-induced mice
|
|
• presumably due to spontaneous production of interferon in induced and un-induced mice
|
|
• following induction with pIpC, blood counts of mature hematopoietic cells is reduced
• cells induced with pIpC, when transplanted into irradiated wild-type mice, causes a lethal failure of hematopoiesis
|
|
• 4 days following induction with pIpC, bone marrow cellularity is reduced 10-fold due to 4.5-fold increase in apoptosis and decreased proliferation
|
|
• in the one mouse that survived 10 days following induction with pIpC
|
|
• in the one mouse that survived 10 days following induction with pIpC
|
|
• following induction with pIpC, hematopoietic progenitor cells are not detected
|
|
• following induction with pIpC, the neutrophil count is reduced to near zero by day 4
|
|
• following induction with pIpC, lymphocyte counts decrease to a greater extent than in similarly treated mice without the cre transgene and do not recover
|
|
• following induction with pIpC, monocyte counts decrease to a greater extent than in similarly treated mice without the cre transgene and do not recover
|
|
• irregular following induction with pIpC
|
|
• following induction with pIpC, red pulp size is reduced with a marked loss of hematopoietic cells
|
|
• following induction with pIpC
|
|
• following induction with pIpC, spleen cellularity is reduced 2-fold
|
|
• following induction with pIpC, white pulp is moderately reduced with increased apoptosis of lymphocytes compared to in mice without the cre transgene
|
|
• presumably due to spontaneous production of interferon in induced and un-induced mice
|
|
• following induction with pIpC, the neutrophil count is reduced to near zero by day 4
|
|
• following induction with pIpC, lymphocyte counts decrease to a greater extent than in similarly treated mice without the cre transgene and do not recover
|
|
• following induction with pIpC, monocyte counts decrease to a greater extent than in similarly treated mice without the cre transgene and do not recover
|
|
• irregular following induction with pIpC
|
|
• following induction with pIpC, red pulp size is reduced with a marked loss of hematopoietic cells
|
|
• following induction with pIpC
|
|
• following induction with pIpC, spleen cellularity is reduced 2-fold
|
|
• following induction with pIpC, white pulp is moderately reduced with increased apoptosis of lymphocytes compared to in mice without the cre transgene
|
|
• following induction with pIpC, mice exhibit an increase in the number of apoptotic enterocytes at the base and along the crypts
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• two weeks after Cre induction by pI-pC injection, the ratio of BP-1+HAShigh cells to BP-1+HASlow cells is much lower than in controls indicating a defect in the transition from pro-B cells to pre-B cells
• there is a 6-fold reduction in the percentage of pro B cells in the bone marrow that are in the S phase
|
|
• bone marrow from mutant mice that have had induction of Cre by pI-pC injection are unable to reconstitute the B cell compartment in irradiated alymphoid mice
• reconstitution still fails when pro B cells are encouraged to differentiate by injection of Igbeta antibodies into the host mice
|
|
• two weeks after Cre induction by pI-pC injection, pre-B cell (B220lowIgM-Cd43-) numbers in the bone marrow are 7% of controls
• immature B cells (B220lowIgM+Cd43-) in the bone marrow are also reduced by a similar amount
|
|
• two weeks after Cre induction by pI-pC injection, the ratio of BP-1+HAShigh cells to BP-1+HASlow cells is much lower than in controls indicating a defect in the transition from pro-B cells to pre-B cells
• there is a 6-fold reduction in the percentage of pro B cells in the bone marrow that are in the S phase
|
|
• bone marrow from mutant mice that have had induction of Cre by pI-pC injection are unable to reconstitute the B cell compartment in irradiated alymphoid mice
• reconstitution still fails when pro B cells are encouraged to differentiate by injection of Igbeta antibodies into the host mice
|
|
• two weeks after Cre induction by pI-pC injection, pre-B cell (B220lowIgM-Cd43-) numbers in the bone marrow are 7% of controls
• immature B cells (B220lowIgM+Cd43-) in the bone marrow are also reduced by a similar amount
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• recombined lymphocytes show increased chromosomal instability and cells in which cre mediated excision occurred are preferentially lost from the bone marrow, thymus, and spleen
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Nijmegen breakage syndrome | DOID:7400 |
OMIM:251260 |
J:93598 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following pI-pC injection to induce cre expression, telomeres undergo end-to-end fusions in quiescent hepatocytes, indicating telomere deprotection, however, hepatocytes are resistant to this damage and are functional in the presence of chromosome end fusions as indicated by normal liver function
• the telomere fusions seen in mutants do not impair liver regeneration after partial hepatectomy as regeneration occurs without cell division involving endoreduplication and cell growth, circumventing the chromosome segregation problems associated with telomere fusions
|
|
• following pI-pC injection to induce cre expression, telomeres undergo end-to-end fusions in quiescent hepatocytes, indicating telomere deprotection, however, hepatocytes are resistant to this damage and are functional in the presence of chromosome end fusions as indicated by normal liver function
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• following pIpC-induction, dendritic cells transplanted into the footpad exhibit normal drainage into lymph nodes
• dendritic cells from pIpC-induced mice exhibit normal migration in 3D matrix
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• death of all mice by 14 days after birth
|
|
• mice display severe reduction in thymus cellularity upon examination at 4-5 days after end of poly(I:C) treatment
|
|
• when sacrificed 4-5 days after end of poly(I:C) treatment, reduced bone marrow cellularity is observed
|
|
• numbers are significantly reduce compared to controls following cre induction
|
|
• numbers are significantly reduce compared to controls following cre induction
|
|
• HSCs are reduced in bone marrow and spleen
|
|
• when sacrificed 4-5 days after end of poly(I:C) treatment, reduced spleen cellularity is observed
|
|
• mice display severe reduction in thymus cellularity upon examination at 4-5 days after end of poly(I:C) treatment
|
|
• numbers are significantly reduce compared to controls following cre induction
|
|
• when sacrificed 4-5 days after end of poly(I:C) treatment, reduced spleen cellularity is observed
|
|
• mice display severe reduction in thymus cellularity upon examination at 4-5 days after end of poly(I:C) treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• most mice die by 3 weeks after pIpC treatment
|
|
• hematopoietic stem cells and progenitor cells from pIpC-treated mice exhibit reduced proliferation in vitro compared with control cells
• however, cells from pIpC-treated mice exhibit normal hematopoietic stem cells maintenance
|
|
• hematopoietic stem cells and progenitor cells from pIpC-treated mice fail to form erythroid colonies on methylcellulose unlike control cells
• hematopoietic stem cells and progenitor cells from pIpC-treated mice for fewer, smaller granulocyte and monocyte colonies on methylcellulose compared with control cells
• however, cells from pIpC-treated mice exhibit normal myeloid colony formation and hematopoietic stem cells maintenance
|
|
• however, cells from pIpC-treated mice exhibit normal myeloid colony formation
• cells from pIpC-treated mice for fewer granulocyte and monocyte colonies on methylcellulose compared with control cells
|
|
• one third of control after pIpC treatment
|
|
• pIpC-treated mice exhibit a 10-fold increased CD41+ megakaryocytes in the marrow compared with control mice
|
|
• white blood cell precursor cells from pIpC-treated mice exhibit over-replication of DNA compared with control cells
|
|
• in the splenic red pulp of mice treated with pIpC
|
|
• hematopoietic stem cells and progenitor cells from pIpC-treated mice fail to form erythroid colonies on methylcellulose unlike control cells
|
|
• pIpC-treated mice exhibit an increase in Lin- Sca1- c-Kit+ CD9+ CD41+ megakaryocyte precursors compared with control mice
• marrow from pIpC-treated mice forms 3 times as many megakaryocyte colonies on methylcellulose due to increased differentiation rather than increased number of progenitor cells compared with control cells
|
|
• pIpC-treated mice exhibit reduced proerythroblasts, basophilic erythroplasts, polychromatophiolic erythroblasts, orthochromatophilic erythroblasts, and reticulocytes compared with control mice
|
|
• pIpC-treated mice exhibit 40%-60% less red blood cells than control mice
|
|
• 5 to 10 times in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit a decrease in Gr1+ Mac1+ leukocytes in the marrow compared with control mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit an increase in Lin- Sca1+ c-Kit+ stem cells compared with control mice
|
|
• paucicellular
|
|
• bone marrow cells from pIpC-treated mice exhibit poor engraftment compared with control cells
|
|
• pIpC-treated mice exhibit increased serum erythropoietin levels compared with control mice
• however, serum thrombopoietin levels are normal
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit a decrease in Gr1+ Mac1+ leukocytes in the marrow compared with control mice
|
|
• in pIpC-treated mice
|
|
• paucicellular
|
|
• hematopoietic stem cells and progenitor cells from pIpC-treated mice exhibit reduced proliferation in vitro compared with control cells
• however, cells from pIpC-treated mice exhibit normal hematopoietic stem cells maintenance
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 4 weeks after treatment with pIpC thymus cellularity is decreased compared to in wild-type mice
• however, thymus cellularity after 2 weeks of treatment with pIpC is normal
|
|
• at 2 and 4 weeks after treatment with pIpC, the numbers of early T cell progenitors is decreased compared to in wild-type mice
|
|
• following treatment with pIpC, double negative relative and absolute cell numbers are decreased compared to in wild-type mice
• following treatment with pIpC, DN2 and DN3 cells are almost completely absent
|
|
• following treatment with pIpC
|
|
• following treatment with pIpC, the number of LSK (lineage - Sca-1 + c-Kit +) cells is decreased 3- to 5-fold in the bone marrow compared to in wild-type mice
• following treatment with pIpC, the number of LSKcells is decreased in the blood and spleen compared to in wild-type mice
• defects in stem cell renewal are cell-autonomous
• following treatment with pIpC, LSK cell cycling is accelerated with loss of quiescence compared to in wild-type mice
• following treatment with pIpC, cultured progenitor cells exhibit reduced colony forming capacity and a loss of self-renewal compared to wild-type cells
• however, the relative abundance of common, megakaryocyte-erythrocyte, and granulocyte-monocyte progenitors and cell cycling of more differentiated progenitor cells than lSK cells are normal
|
|
• 4 weeks after treatment with pIpC thymus cellularity is decreased compared to in wild-type mice
• however, thymus cellularity after 2 weeks of treatment with pIpC is normal
|
|
• at 2 and 4 weeks after treatment with pIpC, the numbers of early T cell progenitors is decreased compared to in wild-type mice
|
|
• following treatment with pIpC, double negative relative and absolute cell numbers are decreased compared to in wild-type mice
• following treatment with pIpC, DN2 and DN3 cells are almost completely absent
|
|
• 4 weeks after treatment with pIpC thymus cellularity is decreased compared to in wild-type mice
• however, thymus cellularity after 2 weeks of treatment with pIpC is normal
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• after induction with PiPc, 6-mo-old mice exhibit no significant differences in serum and urine creatinine levels relative to control mice
|
|
• after induction with IFN at 24-28 days of age, mice exhibit a 75% reduction in serum IGF-I levels relative to control mice, still evident at 53 days of age
(J:55718)
• after induction with PiPc at 4 weeks of age, mice exhibit a 80-85% reduction in serum IGF-I levels relative to control mice, still evident at 24 months of age
(J:121798)
• renal IGF-II mRNA levels are reduced by 79%, suggesting that the effects of circulating IGF-I on kidney size may be mediated by renal IGF-II; however, no differences in serum IGF-II levels are observed at 9 months
(J:121798)
|
|
• after induction with PiPc, mice exhibit compensatory increased circulating GH levels relative to control mice
|
|
• after induction with PiPc, 6-mo-old mice exhibit increased 24-hr potassium excretion relative to control mice
|
|
• after induction with PiPc, 6-mo-old mice exhibit increased 24-hr sodium excretion relative to control mice
|
| N |
• after induction with IFN at 24-28 days of age, mice exhibit normal postnatal body growth up to 53 days of age relative to control mice
(J:55718)
• after induction with PiPc at 4 weeks of age, mice exhibit no significant differences in body weight relative to control mice, as shown at 7 and 24 months of age
(J:121798)
|
| N |
• after induction with PiPc, 6-mo-old mice exhibit no significant differences in serum and urine creatinine levels, GFR, creatinine clearance, or 24-hr urine volume relative to control mice
• no glomerulosclerosis, vascular defects, mesangial sclerosis, or cortical fibrosis is observed at 24 months of age
|
|
• after induction with PiPc, 6-mo-old mice exhibit increased 24-hr potassium excretion relative to control mice
|
|
• after induction with PiPc, 6-mo-old mice exhibit increased 24-hr sodium excretion relative to control mice
|
|
• after induction with PiPc, absolute and relative kidney weight is reduced in 7- and 24-month-old mice relative to control mice
|
|
• after induction with PiPc, 7-mo-old mice exhibit increased systolic blood pressure relative to control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• after ADP stimulation, platelets fail to bind soluble collagen in an inside-out activation assay
• severely defective platelet adhesion to collagen under flow is observed in mutants in an outside-in activation assay
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 38% mortality at day 7 after birth when cre expression is induced with IFN-alpha at days 3, 5, and 7 postnatally
|
|
• seen when Cre expression is induced by IFN-alpha at birth
|
|
• 52% of mice that survive past P7 when Cre expression is induced with IFN-alpha at days 3,5, and 7 postnatally are growth retarded
• however, when IFN-alpha is administered to 6 and 10 week old mice (to induce Cre expression), there are no significant changes in body mass
|
|
• seen when Cre expression is induced with IFN-alpha at birth; hepatocytes of 14 day old mutants are small and rounded and the hepatic sinusoidal architecture remains immature, with persistence of twin cell hepatic plates
• many sinusoids contain prominent eosinophilic histiocytes
|
|
• 14 day old mutants treated with IFN-alpha to induce Cre expression exhibit increased extramedullary hematopoiesis
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• exposure to cadmium was lethal for all male and 2 out of 3 female mutants after induction of cre mediated recombination compared to no male and only 1 female (out of 4) death in mutants without the cre transgene
|
|
• exposure to cadmium was lethal for all male and 2 out of 3 female mutants after induction of cre mediated recombination compared to no male and only 1 female (out of 4) death in mutants without the cre transgene
|
|
• cadmium exposure resulted in cell degeneration and necrosis in the liver, lung, and pancreas in all male mutants and some of the female mutants after induction of cre mediated recombination
|
|
• transgenic mice after induction of cre accumulate less cadmium in the liver and kidneys compared to control transgenic mice that do not carry the cre transgene
|
|
• transgenic mice after induction of cre have one third of the number of white blood cells compared to control transgenic mice that do not carry the cre transgene
|
|
• the lymphocyte population in particular is severely reduced in transgenic mice after induction of cre compared to control transgenic mice that do not carry the cre transgene
|
|
• transgenic mice after induction of cre have one third of the number of white blood cells compared to control transgenic mice that do not carry the cre transgene
|
|
• the lymphocyte population in particular is severely reduced in transgenic mice after induction of cre compared to control transgenic mice that do not carry the cre transgene
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• gene deletion frequency of 60-90% after pIpC injection
|
|
• marked decrease in the ratio of mature to immature megakaryocytes among bone marrow cells
• 10 fold decrease in CFU-MK in bone marrow
|
|
• BFU-E and CFU-E are increased
|
|
• increased erythrocytic cells
|
|
• 33% decrease in the mean number of platelets in the circulation
• mild thrombocytopenia
|
|
• decreased granulocytes
• CFU-G are decreased
|
|
• CFU-M are increased
|
|
• decreased granulocytes
• CFU-G are decreased
|
|
• CFU-M are increased
|
|
• marked decrease in the ratio of mature to immature megakaryocytes among bone marrow cells
• 10 fold decrease in CFU-MK in bone marrow
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• no abnormalities in hematopoiesis are detected
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• gene deletion frequency of 60-90% after pIpC injection
|
|
• marked decrease in the ratio of mature to immature megakaryocytes among bone marrow cells
• 10 fold decrease in CFU-MK in bone marrow
|
|
• 33% decrease in the mean number of platelets in the circulation
• mild thrombocytopenia
|
|
• marked decrease in the ratio of mature to immature megakaryocytes among bone marrow cells
• 10 fold decrease in CFU-MK in bone marrow
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• after Poly(I) Poly(C) induction of cre expression in 6 week old mice, bone marrow shows 10 fold fewer pre-B cells, indicating a block in pre/pre-B differentiation
|
|
• after Poly(I) Poly(C) induction of cre expression in 6 week old mice, 2 fold increase in megakaryocytes is observed
|
|
• after Poly(I) Poly(C) induction of cre expression in 6 week old mice, the total WBC count gradually decreases over a 6 week period resulting from a striking decline in peripheral B lymphocytes
|
|
• after Poly(I) Poly(C) induction of cre expression in 6 week old mice, bone marrow shows 10 fold fewer pre-B cells
|
|
• after Poly(I) Poly(C) induction of cre expression in 6 week old mice, an increase in the hematopoietic stem cells and shift in progenitor fate toward granulocyte differentiation is observed
|
|
• after Poly(I) Poly(C) induction of cre expression in 6 week old mice, an expansion of the splenic red pulp is observed
|
|
• after Poly(I) Poly(C) induction of cre expression in 6 week old mice, bone marrow shows 10 fold fewer pre-B cells, indicating a block in pre/pre-B differentiation
|
|
• after Poly(I) Poly(C) induction of cre expression in 6 week old mice, the total WBC count gradually decreases over a 6 week period resulting from a striking decline in peripheral B lymphocytes
|
|
• after Poly(I) Poly(C) induction of cre expression in 6 week old mice, bone marrow shows 10 fold fewer pre-B cells
|
|
• after Poly(I) Poly(C) induction of cre expression in 6 week old mice, an expansion of the splenic red pulp is observed
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• a large fraction of pre-B and DP thymocytes remain in the S-G2-M phase rather than moving to G0 phase
• double positive (DP) thymocytes, large pre-B cells, small pre-B cells and granulocytes contain more cells in G2-M following 24 hour pulse than controls
|
|
• 4 fold increase in apoptosis of DP thymocytes
|
|
• 5-10 fold reduction in total thymocytes at 2 and 4 weeks following pI:pC administration
|
|
• 4 fold increase in apoptosis of DP thymocytes
|
|
• 5-10 fold reduction in total thymocytes at 2 and 4 weeks following pI:pC administration
|
|
• decreased number of DP thymocytes
|
|
• reduced numbers of peripheral blood B cells at 2 and 4 weeks following pI:pC administration
|
|
• reduced numbers of immature B cells in bone marrow (IgM+ IgD- B220+)
|
|
• reduced numbers of mature recirculating B cells in bone marrow(IgM+ IgD+ B220hi)
|
|
• 2-3 fold reduction in percentage and absolute number of pre-B cells in bone marrow (IgM- B220+ CD43low/-)
|
|
• 4 fold increase in apoptosis of DP thymocytes
|
|
• 5-10 fold reduction in total thymocytes at 2 and 4 weeks following pI:pC administration
|
|
• decreased number of DP thymocytes
|
|
• reduced numbers of peripheral blood B cells at 2 and 4 weeks following pI:pC administration
|
|
• reduced numbers of immature B cells in bone marrow (IgM+ IgD- B220+)
|
|
• reduced numbers of mature recirculating B cells in bone marrow(IgM+ IgD+ B220hi)
|
|
• 2-3 fold reduction in percentage and absolute number of pre-B cells in bone marrow (IgM- B220+ CD43low/-)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• induction of Cyp1A1 and Cyp1a2 by TCDD is absent from the liver, in addition Cyp1a2 constitutive expression is decreased
• hepatic induction of Slc2a1, Aldoa, and Hmox1 by CoCl2, which mimics physiological hypoxia, is variably reduced
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• peripheral B cells are not maintained
|
|
• peripheral T cells are not maintained
|
|
• peripheral B cells are not maintained
|
|
• peripheral T cells are not maintained
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following pI-pC treatment, gamma-irradiated or ENU treated mutants progress to fatal myeloid disease unlike controls
|
|
• within 7 months after pI-pC treated mutants were subjected to a sublethal dose of gamma-irradiation or an injection of ENU, 60% of gamma-irradiated and 73% of ENU-treated mutants succumbed to a spectrum of myeloproliferative diseases compared to none of the controls
• pI-pC treated gamma-irradiated mutants had leukemic infiltrates in the liver, lung, and lymph nodes
|
|
• following pI-pC treatment, saw an increase in Mac-1+/Gr-1+ myeloid cells in bone marrow, indicating myeloid hyperplasia
• 3 weeks following pI-pC treatment, mutants had an average three-fold increase in granulocyte/macrophage progenitors (GMPs) and a three-fold reduction in the number of common lymphoid progenitors (CLPs) in the bone marrow
• enhanced self-renewal/proliferation of myeloid progenitors (hematopoietic stem cells (HSCs), GMPs and common myeloid progenitors (CMPs)) as indicated by their ability to generate colonies upon serial replating
|
|
• following pI-pC treatment, gamma-irradiated or ENU treated mutants developed anemia
|
|
• following pI-pC treatment, gamma-irradiated mutant bone marrow contained pseudo-Gaucher cells, indicating high cell turnover
• following pI-pC treatment, gamma-irradiated and ENU treated mice had a significant increase in either Mac-1+/Gr-1-lo mature monocytes or Mac-1+/Gr-1+ immature myeloid cells and mature neutrophils and decreased B and T cells in the bone marrow
|
|
• following pI-pC treatment, gamma-irradiated or ENU treated mutants developed thrombocytopenia
|
|
• following pI-pC treatment, gamma-irradiated or ENU treated mutants had increased cell counts of mature monocytes and neutrophils
|
|
• following pI-pC treatment, spleens from gamma-irradiated mutants showed extensive disruption of the splenic architecture by poorly differentiated myeloid cells
• following pI-pC treatment, gamma-irradiated and ENU treated mice had a significant increase in either Mac-1+/Gr-1-lo mature monocytes or Mac-1+/Gr-1+ immature myeloid cells and mature neutrophils and decreased B and T cells in the spleen
|
|
• following pI-pC treatment, gamma-irradiated or ENU treated mutants developed splenomegaly
|
|
• following pI-pC treatment, spleens from ENU treated mutants demonstrated marked expansion of red-pulp with megakaryoctyes, prominent erythropoiesis, and well-differentiated myelopoiesis
|
|
• following pI-pC treatment, saw an increase in Mac-1+/Gr-1+ myeloid cells in bone marrow, indicating myeloid hyperplasia
• 3 weeks following pI-pC treatment, mutants had an average three-fold increase in granulocyte/macrophage progenitors (GMPs) and a three-fold reduction in the number of common lymphoid progenitors (CLPs) in the bone marrow
• enhanced self-renewal/proliferation of myeloid progenitors (hematopoietic stem cells (HSCs), GMPs and common myeloid progenitors (CMPs)) as indicated by their ability to generate colonies upon serial replating
|
|
• following pI-pC treatment, gamma-irradiated or ENU treated mutants had increased cell counts of mature monocytes and neutrophils
|
|
• following pI-pC treatment, spleens from gamma-irradiated mutants showed extensive disruption of the splenic architecture by poorly differentiated myeloid cells
• following pI-pC treatment, gamma-irradiated and ENU treated mice had a significant increase in either Mac-1+/Gr-1-lo mature monocytes or Mac-1+/Gr-1+ immature myeloid cells and mature neutrophils and decreased B and T cells in the spleen
|
|
• following pI-pC treatment, gamma-irradiated or ENU treated mutants developed splenomegaly
|
|
• following pI-pC treatment, spleens from ENU treated mutants demonstrated marked expansion of red-pulp with megakaryoctyes, prominent erythropoiesis, and well-differentiated myelopoiesis
|
|
• following pI-pC treatment, gamma-irradiated or ENU treated mutants progress to fatal myeloid disease unlike controls
|
|
• following pI-pC treatment, gamma-irradiated or ENU treated mutants developed splenomegaly
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 50% reduction in thymus weight
|
|
• 54% reduction in total thymocyte number
|
|
• although double negative T cell numbers are normal, double positive T cell numbers are reduced about 60%
|
|
• 50% reduction in thymus weight
|
|
• 54% reduction in total thymocyte number
|
|
• although double negative T cell numbers are normal, double positive T cell numbers are reduced about 60%
|
|
• 50% reduction in thymus weight
|
|
• 54% reduction in total thymocyte number
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 71% of mice treated with pIpC, G-CSF, and ENU exhibit thymic tumors, splenomegaly, and/or death 10 months after treatment
|
| N |
• mice exhibit normal peripheral blood cell counts up to 1.5 years following induction with pIpC at 6 weeks
|
|
• at 1.5 years of age, 29% of enlarged spleens from mice induced with pIpC at 6 weeks exhibit myeloproliferative disorder compared to 7% of wild-type enlarged spleens
|
|
• after 4 weeks of pIpC induction, the frequency of hematopoietic stem cells in the bone marrow is decreased compared to in wild-type mice
• however, at 1.5 years of age pIpC-induced mice exhibit a normal of hematopoeitic stem cells
|
|
• at 3 months, spleen structure in mice induced with pIpC at 6 weeks is moderately effaced unlike in wild-type mice
|
|
• at 3 months, one mouse induced with pIpC at 6 weeks exhibited an enlarged spleen
• at 1.5 years of age, 47% of mice induced with pIpC at 6 weeks exhibit enlarged spleen compared to 20% in Tg(Mx1-cre)1Cgn mice
• 71% of mice treated with pIpC, G-CSF, and ENU exhibit thymic tumors, splenomegaly, and/or death 10 months after treatment
|
|
• at 1.5 years of age in mice induced with pIpC at 6 weeks
|
|
• mice treated with pIpC, G-CSF, and ENU exhibit myeloid and lymphoid neoplasias
|
|
• 71% of mice treated with pIpC, G-CSF, and ENU exhibit thymic tumors, splenomegaly, and/or death 10 months after treatment
|
|
• in one mouse induced with pIpC at 6 weeks
|
|
• in one 9 month old in mouse induced with pIpC at 6 weeks
|
|
• at 1.5 years of age, 29% of enlarged spleens from mice induced with pIpC at 6 weeks exhibit myeloproliferative disorder compared to 7% of wild-type enlarged spleens
|
|
• at 3 months, spleen structure in mice induced with pIpC at 6 weeks is moderately effaced unlike in wild-type mice
|
|
• at 3 months, one mouse induced with pIpC at 6 weeks exhibited an enlarged spleen
• at 1.5 years of age, 47% of mice induced with pIpC at 6 weeks exhibit enlarged spleen compared to 20% in Tg(Mx1-cre)1Cgn mice
• 71% of mice treated with pIpC, G-CSF, and ENU exhibit thymic tumors, splenomegaly, and/or death 10 months after treatment
|
|
• at 1.5 years of age in mice induced with pIpC at 6 weeks
|
|
• 71% of mice treated with pIpC, G-CSF, and ENU exhibit thymic tumors, splenomegaly, and/or death 10 months after treatment
|
|
• 71% of mice treated with pIpC, G-CSF, and ENU exhibit thymic tumors, splenomegaly, and/or death 10 months after treatment
|
|
• at 3 months, one mouse induced with pIpC at 6 weeks exhibited an enlarged spleen
• at 1.5 years of age, 47% of mice induced with pIpC at 6 weeks exhibit enlarged spleen compared to 20% in Tg(Mx1-cre)1Cgn mice
• 71% of mice treated with pIpC, G-CSF, and ENU exhibit thymic tumors, splenomegaly, and/or death 10 months after treatment
|
|
• in one mouse induced with pIpC at 6 weeks
|
|
• in one 9 month old in mouse induced with pIpC at 6 weeks
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• fewer than expected mice are present at weaning
|
|
• bone marrow cells from pIpC-induced mice form fewer granulocyte-macrophage positive colonies than when wild-type cells are used
• bone marrow cells transplanted into wild-type mice and induced with pIpC fail to reconstitute multiple hematopoietic lineages
• however, treatment with imatinib restores the ability of pIpC-treated bone marrow cells to induce long-term multiple lineages reconstitution in transplantation experiments
|
|
• bone marrow cells from pIpC-induced mice form fewer granulocyte, erythrocyte, macrophage, and megakaryocyte positive colonies than when wild-type cells are used
|
|
• all pIpC-induced mice develop a chronic myelocytic leukemia (CML)-like myeloproliferative disease
• bone marrow cells activated with pIpC induce develop a CML-like myeloproliferative disease when transplanted into wild-type mice
• however, secondary transplantation of neoplastic cells or fractionated splenocytes are highly inefficient at inducing myeloproliferative disease
|
|
• in pIpC-induced mice
|
|
• 2 weeks after pIpC induction, bone marrow and spleens exhibit a decreased in the frequency of lymphoid and erythroid lineages but an increase in myeloid lineages compared to control mice
|
|
• in pIpC-induced mice despite treatment with imatinib
|
|
• after pIpC induction, mice exhibit severe myeloid leukocytosis with a 25-fold increase in white blood cells compared with similarly treated wild-type mice
• however, treatment with imatinib reduces white blood cell counts to wild-type levels
|
|
• the number of Mac1+Gr1+ myeloid cells in the spleen and bone marrow of pIpC-induced mice is increased compared to in wild-type mice
|
|
• severe following pIpC induction
|
|
• the frequency of hematopoietic stem cells in the bone marrow of pIpC-induced mice is decreased compared to in wild-type mice
• the number of hematopoietic stem cells in the bone marrow of pIpC-induced mice is less than in wild-type mice
• bone marrow cells transplanted into wild-type mice and activated with pIpC inhibit normal bone marrow hematopoietic stem cells and result in a decrease in donor and recipient-type hematopoietic stem cells compared to when wild-type bone marrow cells are transplanted
• however, treatment of pIpC-induced mice with imatinib returns the frequency of hematopoietic stem cell to near normal even in transplantation experiments
|
|
• the absolute number of hematopoietic stem cells in the spleen is increased in pIpC-induced mice compared to in wild-type mice
|
|
• pIpC-induced mice exhibit splenic architecture effacement unlike similarly treated wild-type mice
• however, treatment with imatinib returns spleen architecture to normal
• 2 weeks after pIpC induction, bone marrow and spleens exhibit a decreased in the frequency of lymphoid and erythroid lineages but an increase in myeloid lineages compared to control mice
|
|
• 10-fold 72 hours after pIpC induction unlike similarly treated wild-type mice
• however, treatment with imatinib reduces liver size to wild-type and clears neoplastic cells
|
|
• following pIpC induction
|
|
• in pIpC-induced mice
|
|
• in pIpC-induced mice
|
|
• pIpC-induced mice loss organized splenic follicle cells unlike similarly treated wild-type mice
|
|
• when bone marrow cells are transplanted into recipient mice and induced with pIpC recipient mice exhibit enlarge spleen, effacement of spleen architecture, and increased white blood cell counts compared to when mice are transplanted with control bone marrow cells lacking the cre transgene
• however, treatment with imatinib decreased white blood cell counts in recipients following pIpC-induction of transplanted bone marrow cells
• bone marrow cells transplanted into wild-type mice and activated with pIpC inhibit normal bone marrow hematopoietic stem cells and result in a decrease in donor and recipient-type hematopoietic stem cells compared to when wild-type bone marrow cells are transplanted
|
|
• neoplastic cells in the livers and spleens of pIpC-induced mice are positive for proliferative markers
|
|
• 25% of un-induced mice develop a chronic myelocytic leukemia (CML)-like disease unlike control mice
• pIpC-induced mice exhibit a CML-like myeloproliferative disease unlike similarly treated wild-type mice
• bone marrow cells activated with pIpC induce develop a CML-like myeloproliferative disease when transplanted into wild-type mice
• however, secondary transplantation of neoplastic cells or fractionated splenocytes are highly inefficient at inducing myeloproliferative disease
• treatment with imatinib increases the frequency of leukemia initiating cells in transplantation experiments with pIpC-activated whole bone marrow cells and hematopoietic stem cells and results in greater incidence of CML-like disease
• leukemia cells infiltrate the lungs in pIpC-induced mice
|
|
• pIpC-induced mice exhibit mature myeloid cells surrounding portal cavities and infiltrating the parenchyme unlike in similarly treated wild-type mice
|
|
• 2-fold 72 hours after pIpC induction unlike similarly treated wild-type mice
• however, treatment with imatinib reduces liver size to wild-type and clears neoplastic cells
|
|
• following pIpC induction
|
|
• pIpC-induced mice exhibit mature myeloid cells infiltrating the parenchyme unlike in similarly treated wild-type mice
|
|
• pIpC-induced mice exhibit mature myeloid cells infiltrating the lungs unlike in similarly treated wild-type mice
• leukemia cells infiltrate the lungs in pIpC-induced mice
|
|
• all pIpC-induced mice develop a chronic myelocytic leukemia (CML)-like myeloproliferative disease
• bone marrow cells activated with pIpC induce develop a CML-like myeloproliferative disease when transplanted into wild-type mice
• however, secondary transplantation of neoplastic cells or fractionated splenocytes are highly inefficient at inducing myeloproliferative disease
|
|
• after pIpC induction, mice exhibit severe myeloid leukocytosis with a 25-fold increase in white blood cells compared with similarly treated wild-type mice
• however, treatment with imatinib reduces white blood cell counts to wild-type levels
|
|
• the number of Mac1+Gr1+ myeloid cells in the spleen and bone marrow of pIpC-induced mice is increased compared to in wild-type mice
|
|
• severe following pIpC induction
|
|
• pIpC-induced mice exhibit splenic architecture effacement unlike similarly treated wild-type mice
• however, treatment with imatinib returns spleen architecture to normal
• 2 weeks after pIpC induction, bone marrow and spleens exhibit a decreased in the frequency of lymphoid and erythroid lineages but an increase in myeloid lineages compared to control mice
|
|
• 10-fold 72 hours after pIpC induction unlike similarly treated wild-type mice
• however, treatment with imatinib reduces liver size to wild-type and clears neoplastic cells
|
|
• following pIpC induction
|
|
• in pIpC-induced mice
|
|
• in pIpC-induced mice
|
|
• pIpC-induced mice loss organized splenic follicle cells unlike similarly treated wild-type mice
|
|
• 2-fold 72 hours after pIpC induction unlike similarly treated wild-type mice
• however, treatment with imatinib reduces liver size to wild-type and clears neoplastic cells
|
|
• following pIpC induction
|
|
• 10-fold 72 hours after pIpC induction unlike similarly treated wild-type mice
• however, treatment with imatinib reduces liver size to wild-type and clears neoplastic cells
|
|
• following pIpC induction
|
|
• in pIpC-induced mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• there is an increase in the number of smaller-sized megakaryocytes that formed from progenitor cells from pIpC-induced mice than from Rbm15tm1Swm control cells
• however, the number of megakaryocytic colony-forming progenitors is the same as in Rbm15tm1Swm control mice
• in liquid culture, Lin- bone marrow cells from pIpC-induced mice differentiate into more, smaller CD41+ megakaryocyte cells than similarly treated Rbm15tm1Swm control cells
|
|
• bone marrow cells from pIpC-induced mice transplanted into a lethally irradiated recipient contribute less to lymphomyelopoiesis than bone marrow cells from Rbm15tm1Swm control mice
• however, hematopoietic stem cells exhibit normal homing, proliferation, in vitro differentiation, and survival
• in serial transplantation assays, bone marrow cells from pIpC-induced mice are less competitive than cells from Rbm15tm1Swm control mice
|
|
• the number of CD41+ megakaryocytes in the bone marrow and spleen of pIpC-induced mice is greater than in Rbm15tm1Swm control mice
• histopathologically, the number of megakaryocytes in the spleen of pIpC-induced mice is greater than in Rbm15tm1Swm control mice
• however, histopathologically the number of megakaryocytes in the bone marrow of pIpC-induced mice is the same as in Rbm15tm1Swm control mice and over expression of c-Myc partially rescues the increase in megakaryocyte numbers
|
|
• in pIpC-induced mice compared to Rbm15tm1Swm control mice
|
|
• in pIpC-induced mice compared to Rbm15tm1Swm control mice
|
|
• in pIpC-induced mice compared to Rbm15tm1Swm control mice
|
|
• in pIpC-induced mice compared to Rbm15tm1Swm control mice
|
|
• the percent of LSK+ cells, enriched for both long-term and short-term hematopoietic stem cells (ST-HSC and LT-HSC), in the bone marrow of pIpC-induced mice is increased compared to in Rbm15tm1Swm control mice
• the percentage of LT-HSCs in the bone marrow of pIpC-induced mice is 2-fold higher than Rbm15tm1Swm control mice
• the absolute number of LT-HSCs in the bone marrow of pIpC-induced mice is higher than in Rbm15tm1Swm control mice
• however, the percentage of ST-HSCs is normal
• the percent and number of LT-HSCs are increased in recipients of bone marrow cells from pIpC-induced mice compared to cells from Rbm15tm1Swm control mice
|
|
• in pIpC-induced mice compared to Rbm15tm1Swm control mice
|
|
• in pIpC-induced mice compared to Rbm15tm1Swm control mice
|
|
• in pIpC-induced mice compared to Rbm15tm1Swm control mice
|
|
• in pIpC-induced mice compared to Rbm15tm1Swm control mice
|
|
• in pIpC-induced mice compared to Rbm15tm1Swm control mice
|
|
• there is an increase in the number of smaller-sized megakaryocytes that formed from progenitor cells from pIpC-induced mice than from Rbm15tm1Swm control cells
• however, the number of megakaryocytic colony-forming progenitors is the same as in Rbm15tm1Swm control mice
• in liquid culture, Lin- bone marrow cells from pIpC-induced mice differentiate into more, smaller CD41+ megakaryocyte cells than similarly treated Rbm15tm1Swm control cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following pIpC induction cultured precursor cells fail to produce plasmacytoid dendritic cells
|
|
• following pIpC induction cultured precursor cells fail to produce plasmacytoid dendritic cells
|
|
• mild decrease in the total number of cells in GM-CSF-supplemented cultures following pIpC treatment
|
|
• following pIpC induction cultured precursor cells fail to produce plasmacytoid dendritic cells and in vivo
|
|
• in Flt3L-supplemented cultures following pIpC induced deletion in hematopoietic stem cells and in vivo
|
|
• following pIpC induction cultured precursor cells fail to produce plasmacytoid dendritic cells
|
|
• mild decrease in the total number of cells in GM-CSF-supplemented cultures following pIpC treatment
|
|
• following pIpC induction cultured precursor cells fail to produce plasmacytoid dendritic cells and in vivo
|
|
• in Flt3L-supplemented cultures following pIpC induced deletion in hematopoietic stem cells and in vivo
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• basal cholesterol efflux from cholesterol-loaded macrophages to HDL is reduced
|
|
• basal cholesterol efflux from cholesterol-loaded macrophages to HDL is reduced
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in lethally irradiated host when transplanted with bone marrow cells
|
|
• decreased number and increased fraction of apoptotic common myeloid progenitors granulocyte-monocyte progenitors and megakaryocyte-erythroid progenitors following pIpC treatment
|
|
• decreased myeloid cells in bone marrow and spleen at 21 days post pIpC treatment every other day for 5 days
• impact on myeloid compartment is more profound than B and T cell compartments
|
|
• at 21 days post pIpC treatment every other day for 5 days
|
|
• decreased in number and increased fraction of apoptotic in pIpC-treated mice
|
|
• at 21 days post pIpC treatment every other day for 5 days
|
|
• in peripheral blood following pIpC treatment
|
|
• in peripheral blood following pIpC treatment
|
|
• in peripheral blood following pIpC treatment
|
|
• in peripheral blood but not significantly depleted in the thymus
|
|
• in bone marrow and spleen at 21 days post pIpC treatment every other day for 5 days
|
|
• decrease in the number of T-lineage (CD3+) cells in bone marrow and spleen at 21 days post pIpC treatment every other day for 5 days
|
|
• following pIpC treatment
• decreased total number of multipotent progenitors following pIpC treatment
• percentage of cell death of hematopoietic stem cells and multipotent progenitors are similar to control
|
|
• at 21 days post pIpC treatment every other day for 5 days
|
|
• decreased myeloid cells in bone marrow and spleen at 21 days post pIpC treatment every other day for 5 days
• impact on myeloid compartment is more profound than B and T cell compartments
|
|
• in peripheral blood following pIpC treatment
|
|
• in peripheral blood following pIpC treatment
|
|
• in peripheral blood but not significantly depleted in the thymus
|
|
• in bone marrow and spleen at 21 days post pIpC treatment every other day for 5 days
|
|
• decrease in the number of T-lineage (CD3+) cells in bone marrow and spleen at 21 days post pIpC treatment every other day for 5 days
|
|
• at 21 days post pIpC treatment every other day for 5 days
|
|
• significantly increased fraction of cells in S and G2/M phases in bone marrow cells of 2 hours post pIpC-treated animals, with lesser increase in the myeloid progenitors
|
|
• in lethally irradiated host when transplanted with bone marrow cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• of pro-B cells from pIpC-treated mice exposed to IL7
|
|
• of pro-B cells from pIpC-treated mice exposed to IL7
|
|
• reduced frequency in pIpC-treated mice
|
|
• reduced in pro-B cells
|
|
• lower frequency of early (fraction B) and late (fraction C) pro-B cell in pIpC-treated mice
• higher frequency of pre-pro-B cells in pIpC-treated mice
• however, the number of pre-pro-B cells is normal
|
|
• reduced numbers in pIpC-treated mice
|
|
• severely decreased numbers in pIpC-treated mice
|
|
• severely decreased numbers in pIpC-treated mice
|
|
• at the early stage of B-lineage cells in the bone marrow of pIpC-treated mice
|
|
• in the bone marrow and spleen of pIpC-treated mice
|
|
• by half in pIpC-treated mice
|
|
• reduced frequency in pIpC-treated mice
|
|
• of pro-B cells from pIpC-treated mice exposed to IL7
|
|
• of pro-B cells from pIpC-treated mice exposed to IL7
|
|
• of pro-B cells from pIpC-treated mice exposed to IL7
|
|
• of pro-B cells from pIpC-treated mice exposed to IL7
|
|
• reduced frequency in pIpC-treated mice
|
|
• reduced in pro-B cells
|
|
• lower frequency of early (fraction B) and late (fraction C) pro-B cell in pIpC-treated mice
• higher frequency of pre-pro-B cells in pIpC-treated mice
• however, the number of pre-pro-B cells is normal
|
|
• reduced numbers in pIpC-treated mice
|
|
• severely decreased numbers in pIpC-treated mice
|
|
• severely decreased numbers in pIpC-treated mice
|
|
• at the early stage of B-lineage cells in the bone marrow of pIpC-treated mice
|
|
• pIpC-treated mice exhibit a mild decrease in lymphoid-primed multipotent progenitors compared with control mice
|
|
• pIpC-treated mice exhibit a reduction in common lymphoid progenitors highly expressing AA4.1/Cd93 compared with control mice
|
|
• in the bone marrow and spleen of pIpC-treated mice
|
|
• by half in pIpC-treated mice
|
|
• reduced frequency in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• no ectopic B cell development in the thymus is observed after injection of mutant bone marrow progenitors into irradiated wild-type hosts
|
|
• hematopoietic stem cells do not develop in to B cells after 18 days in culture
|
|
• loss of MZ B cells in spleen is detected
|
|
• hematopoietic stem cells do not develop in to B cells after 18 days in culture
|
|
• loss of MZ B cells in spleen is detected
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pIpC-treated mice exhibit abnormal liver histology compared with wild-type mice
|
|
• in pIpC-treated mice
|
|
• liver cells from pIpC-treated mice exhibit ribosomal subunit joining defects compared with cells from wild-type cells
|
|
• in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• hematopoietic cells display increased resistance to endotoxic and polymicrobial septic shock due to attenuated inflammation
|
|
• after bacterial lipopolysaccharide (LPS) challenges
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• median survival is 41 days post pIpC treatment
|
|
• in diseased pIpC-treated mice
|
|
• lymphoid infiltration in the thymus at 6 months in pIpC-treated mice
|
|
• in diseased pIpC-treated mice
|
|
• monomorphic, enlarged white blood cells with a high nuclear:chromatin ratio (consistent with leukemic blasts) at 6 months in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• nearly all B cells are arrested in the early pro-B stage of pIpC-treated mice
|
|
• in the thymus of pIpC-treated mice
|
|
• in the spleen of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• at 6 months in pIpC-treated mice
|
|
• in the thymus of pIpC-treated mice
|
|
• immature single positive cells in the thymus of pIpC-treated mice
|
|
• large, unstained cells (abnormal blasts) in the peripheral blood at 6 months in pIpC-treated mice
|
|
• disrupted separation between white and red pulp by infiltrating lymphoblasts at 6 months in pIpC-treated mice
|
|
• in diseased pIpC-treated mice
|
|
• lymphoid infiltration in the spleen, interstitial and perivascular space of the kidney, perivascular cuffs in the liver, meninges surrounding the brain, thymus, stomach and intestine at 6 months in pIpC-treated mice
|
|
• lymphoid infiltration in the intestine at 6 months in pIpC-treated mice
|
|
• lymphoid infiltration in the stomach at 6 months in pIpC-treated mice
|
|
• lymphoid infiltration in the meninges surrounding the brain at 6 months in pIpC-treated mice
|
|
• lymphoid infiltration in the perivascular cuffs in the liver at 6 months in pIpC-treated mice
|
|
• lymphoid infiltration in the interstitial and perivascular space of the kidney at 6 months in pIpC-treated mice
|
|
• lymphoid infiltration in the intestine at 6 months in pIpC-treated mice
|
|
• lymphoid infiltration in the stomach at 6 months in pIpC-treated mice
|
|
• pIpC-treated mice rapidly develop and succumb to acute leukemia
|
|
• in diseased pIpC-treated mice
|
|
• in diseased pIpC-treated mice
|
|
• in diseased pIpC-treated mice
|
|
• in diseased pIpC-treated mice
|
|
• in diseased pIpC-treated mice
|
|
• lymphoid infiltration in the perivascular cuffs in the liver at 6 months in pIpC-treated mice
|
|
• lymphoid infiltration in the meninges surrounding the brain at 6 months in pIpC-treated mice
|
|
• in diseased pIpC-treated mice
|
|
• lymphoid infiltration in the interstitial and perivascular space of the kidney at 6 months in pIpC-treated mice
|
|
• in diseased pIpC-treated mice
|
|
• lymphoid infiltration in the thymus at 6 months in pIpC-treated mice
|
|
• in diseased pIpC-treated mice
|
|
• severely at 6 months in pIpC-treated mice
|
|
• monomorphic, enlarged white blood cells with a high nuclear:chromatin ratio (consistent with leukemic blasts) at 6 months in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• nearly all B cells are arrested in the early pro-B stage of pIpC-treated mice
|
|
• in the thymus of pIpC-treated mice
|
|
• in the spleen of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• at 6 months in pIpC-treated mice
|
|
• in the thymus of pIpC-treated mice
|
|
• immature single positive cells in the thymus of pIpC-treated mice
|
|
• large, unstained cells (abnormal blasts) in the peripheral blood at 6 months in pIpC-treated mice
|
|
• disrupted separation between white and red pulp by infiltrating lymphoblasts at 6 months in pIpC-treated mice
|
|
• in diseased pIpC-treated mice
|
|
• lymphoid infiltration in the thymus at 6 months in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pIpC injected mice exhibit a modest (24%) increase in goblet cells 10 days after pIpC treatment and this difference resolves by 8 weeks indicting a transient goblet cell hyperplasia
|
|
• mice injected with polyinosinic-polycytidylic acid (pIpC) exhibit thymus cellularity reduced by about 4- to 5-fold compared to controls
• however, bone marrow or splenic cellularity are not affected
• mice injected with pIpC show reduced numbers of all thymic T cell subsets
|
|
• mice injected with polyinosinic-polycytidylic acid (pIpC) exhibit thymus cellularity reduced by about 4- to 5-fold compared to controls
• however, bone marrow or splenic cellularity are not affected
• mice injected with pIpC show reduced numbers of all thymic T cell subsets
|
|
• competitive transplant assays show a modest cell-autonomous loss of B cell subsets generated by pIpC treated mutant bone marrow
• however, pIpC injected mice do not develop myeloproliferative disease, show normal myeloid cell development, and show unaffected hematopoietic stem/progenitor cell numbers
|
|
• pIpC injected mice show an approximate 2-fold loss of NK cell numbers
|
|
• competitive transplant assays show a 3-5 fold reduction in peripheral T cells generated by pIpC treated mutant bone marrow
|
|
• mice injected with polyinosinic-polycytidylic acid (pIpC) exhibit thymus cellularity reduced by about 4- to 5-fold compared to controls
• however, bone marrow or splenic cellularity are not affected
• mice injected with pIpC show reduced numbers of all thymic T cell subsets
|
|
• competitive transplant assays show a modest cell-autonomous loss of B cell subsets generated by pIpC treated mutant bone marrow
• however, pIpC injected mice do not develop myeloproliferative disease, show normal myeloid cell development, and show unaffected hematopoietic stem/progenitor cell numbers
|
|
• pIpC injected mice show an approximate 2-fold loss of NK cell numbers
|
|
• competitive transplant assays show a 3-5 fold reduction in peripheral T cells generated by pIpC treated mutant bone marrow
|
|
• mutant bone marrow stem cells transduced with Notch1 mutants and transplanted into recipient mice which when injected with pIpC show impaired initiation and maintenance of Notch-induced T cell acute lymphoblastic leukemia
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• pIpC-treated mice exhibit normal numbers of megakaryocytes in the bone marrow
|
|
• pIpC-treated mice exhibit abnormal morphology of terminally differentiated megakaryocytes
|
|
• giant platelets with increased number of microtubule coils in pIpC-treated mice
|
|
• severe in pIpC-treated mice whether or not mice are splenectomized
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice whether or not mice are splenectomized
|
|
• pIpC-treated mice exhibit abnormal morphology of terminally differentiated megakaryocytes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice treated with pIpC at 6 weeks of age (to induce human HIP1 expression in the adult hematopoietic system, liver, and kidney) exhibit normal weight at 5.5-6 months of age, indicating rescue of the weight loss observed in Hip1tm5.1(HIP1)Tsr homozygotes
|
| N |
• mice treated with pIpC at 6 weeks of age exhibit no spinal defects at 4 months of age, indicating rescue of the kypholordotic phenotype observed in Hip1tm5.1(HIP1)Tsr homozygotes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• mice treated with polyinosinic-polycytidylic acid [poly(I:C)] for 5 days to induce cre-expression exhibit livers enlarged by 60%
|
|
|
• hepatocytes are hypertrophic in poly(I:C)-treated mice
• hepatocytes of poly(I:C)-treated mice show massive accumulation of endocytic and autophagic vacuoles
|
|
|
• cultured hepatocytes from poly(I:C)-treated mice show decreased autophagic clearance
• however, hepatocytes show normal acidification and delivery of endocytic cargo to lysosomes and autolysosomes
|
|
|
• cultured hepatocytes from poly(I:C)-treated mice show decreased autophagic clearance
|
|
|
• cultured hepatocytes from poly(I:C)-treated mice show decreased autophagic clearance
|
|
|
• mice treated with polyinosinic-polycytidylic acid [poly(I:C)] for 5 days to induce cre-expression exhibit livers enlarged by 60%
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice develop acute leukemia with an incidence of 59% at 12 months of age
• leukemia cells are present in the bone marrow, spleen, lymph nodes and infiltrate multiple organs, including the CNS
• 94% of leukemias have a B cell precursor phenotype
|
|
• in leukemic mice
|
|
• leukemic blasts are arrested at the pro/pre-B stage of B cell precursor differentiation
|
|
• in leukemic mice
|
|
• a lower percentage of B cells are seen in the peripheral blood over a 30 week period in healthy preleukemic mice
|
|
• decrease in immature and recirculating B cells in the bone marrow in healthy preleukemic mice
|
|
• leukemic mice present with leukocytosis
|
|
• in leukemic mice
|
|
• leukemic blasts are arrested at the pro/pre-B stage of B cell precursor differentiation
|
|
• a lower percentage of B cells are seen in the peripheral blood over a 30 week period in healthy preleukemic mice
|
|
• decrease in immature and recirculating B cells in the bone marrow in healthy preleukemic mice
|
|
• leukemic mice present with leukocytosis
|
|
• in leukemic mice
|
|
• in leukemic mice
|
|
• in leukemic mice
|
|
• in leukemic mice
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| acute lymphoblastic leukemia | DOID:9952 |
OMIM:247640 OMIM:613065 |
J:226241 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• mice treated with polyinosinic-polycytidylic acid [poly(I:C)] for 5 days to induce cre-expression exhibit livers enlarged by 60%
|
|
|
• hepatocytes are hypertrophic in poly(I:C)-treated mice
• hepatocytes of poly(I:C)-treated mice show massive accumulation of endocytic and autophagic vacuoles
|
|
|
• cultured hepatocytes from poly(I:C)-treated mice show decreased autophagic clearance
• however, hepatocytes show normal acidification and delivery of endocytic cargo to lysosomes and autolysosomes
|
|
|
• cultured hepatocytes from poly(I:C)-treated mice show decreased autophagic clearance
|
|
|
• cultured hepatocytes from poly(I:C)-treated mice show decreased autophagic clearance
|
|
|
• mice treated with polyinosinic-polycytidylic acid [poly(I:C)] for 5 days to induce cre-expression exhibit livers enlarged by 60%
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• survival of polyinosinic-polycytidylic acid [poly(I:C)] treated mice is impaired
|
|
• lethally irradiated wild-type mice transplanted with mutant whole bone marrow cells show full reconstitution of the bone marrow, normal hemoglobin, elevated white blood cell counts with lymphocytosis, and bone marrow with mildly dysplastic hypolobulated micro-megakaryoctyes in atypical locations 8 weeks after poly(I:C) induction and mice develop elevated platelet count over time
|
|
• 15 months after poly(I:C) treatment, mice show a near-complete loss of myeloid progenitor cells
|
|
• 8 weeks after poly(I:C) treatment, a reduction in bone marrow cellularity and in the percentage of long-term (LT; LinlowSca-1+ckit+CD150+CD48-) and short-term (ST; LinlowSca-1+ckit+CD150-CD48-) hematopoietic stem cells is seen
|
|
• hypolobulated micro-megakaryocytes are seen 8 weeks after poly(I:C) induction
• whole bone marrow cells cultured in vitro in the presence of thrombopoietin show that CD41+ megakaryocytes shift toward hypoploidy
|
|
• reduction of the myeloid lineage 15 months after poly(I:C) induction
|
|
• 8 weeks after poly(I:C) treatment, a reduction in the percentage of long-term (LT; LinlowSca-1+ckit+CD150+CD48-) and short-term (ST; LinlowSca-1+ckit+CD150-CD48-) hematopoietic stem cells is seen
15 months after poly(I:C) treatment, mice show a decrease in the LT-HSCs and ST-HSCs
|
|
• 15 months after poly(I:C) treatment, mice develop pancytopenia
|
|
• reduction of the erythroid lineage 15 months after poly(I:C) induction
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die 5-17 days after induction with polyinosinic-polycytidylic acid [poly(I:C)]
|
|
• areas of the myocardium show wavy fibers with loss of transversal striations, partially with loss of the cell nucleus following poly(I:C) induction
|
|
• myocardium shows signs of ischemia following poly(I:C) induction
|
|
• mice exhibit a decrease in all peripheral blood counts after induction with poly(I:C)
|
|
• seen following poly(I:C) induction
|
|
• 10 days after poly(I:C) treatment, mice show a reduction in hematopoietic stem cells (LSK; LinlowSca-1+ckit+), including long-term (LT; LinlowSca-1+ckit+CD150+CD48-) and short-term (ST; LinlowSca-1+ckit+CD150-CD48-) hematopoietic stem cells and multipotent progenitor cells (MPPs; LinlowSca-1+ckit+CD150-CD48+)
|
|
• rarefication of the red pulp is seen following poly(I:C) induction
|
|
• a greater number of LSK cells are undergoing early and late apoptosis after induction with poly(I:C) compared to controls
• hematopoietic stem cells (HSC) from mice induced with poly(I:C) exit quiescence and enter the cell cycle, with a decrease in the number of HSC (LSK) in G0 and an increase in S/G2/M compared to control cells
|
|
• mice show evidence of fulminant bone marrow failure with evidence of ischemia in multiple organs after induction with poly(I:C)
• lethally irradiated wild-type mice transplanted with mutant whole bone marrow cells become moribund with bone marrow failure 8-14 days after poly(I:C) treatment, with a complete loss of HSPCs
|
|
• rarefication of the red pulp is seen following poly(I:C) induction
|
|
• mice show evidence of fulminant bone marrow failure with evidence of ischemia in multiple organs after induction with poly(I:C)
• lethally irradiated wild-type mice transplanted with mutant whole bone marrow cells become moribund with bone marrow failure 8-14 days after poly(I:C) treatment, with a complete loss of HSPCs
|
|
• cytoplasmic vacuolization and pyknotic nuclei are seen in the liver following poly(I:C) induction
|
|
• liver shows signs of ischemia following poly(I:C) induction
|
|
• areas of the myocardium show wavy fibers with loss of transversal striations, partially with loss of the cell nucleus following poly(I:C) induction
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• uninduced mice exhibit an increase in tetramer+ T cells due to leaky cre expression
|
|
• TCR-switched T cells treated with pIpC induce sterile inflammation in recipient mice possibly due to autoimmune activation
• however, recipient mice treated with galactosylceramide do not exhibit induction of NK T cell differentiation of TCR-switched tetramer+ T cells
|
|
• uninduced mice exhibit an increase in tetramer+ T cells due to leaky cre expression
|
|
• TCR-switched T cells treated with pIpC induce sterile inflammation in recipient mice possibly due to autoimmune activation
• however, recipient mice treated with galactosylceramide do not exhibit induction of NK T cell differentiation of TCR-switched tetramer+ T cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• pIpC-treated mice exhibit normal mature NK T cell maintenance, identity and secretion of cytokines
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• due to acute myeloid leukemia, survival of pIpC-treated mice is 617 days compared with 769 days for wild-type mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• with serial replating, cells from pIpC-treated mice exhibit increased myeloid progenitor colony formation on methylcellulose compared with cells from wild-type mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit a decrease in late B cells (B220+ CD19+) compared with wild-type mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• acute myeloid leukemia with maturation in pIpC-treated mice
|
|
• in 6 of 13 pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit a decrease in late B cells (B220+ CD19+) compared with wild-type mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in the bone marrow of pIpC-treated mice
|
|
• in the bone marrow of pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in the bone marrow of old mice treated with pIpC
|
|
• in the bone marrow of old mice treated with pIpC
|
|
• pIpC-treated mice exhibit less recirculating B cells compared to in similarly treated control mice
|
|
• in the bone marrow of old mice treated with pIpC
|
|
• pIpC-treated mice fail to exhibit age-related decline in B lineage precursors (pro-B, pre-B, and immature B cells) in the bone marrow compared to in control mice
|
|
• in the bone marrow of old mice treated with pIpC
|
|
• in the bone marrow of old mice treated with pIpC
|
|
• in the bone marrow of old mice treated with pIpC
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at 20 weeks after pIpC induction, bones are pale, suggesting decreased erythropoiesis
• at 20 weeks after pIpC induction, erythroid TER-119+ cells are reduced in the bone marrow but a compensatory increase is seen in the spleen
|
|
• at 20 weeks after pIpC induction, myeloid cells are the predominant cell population in the bone marrow and are increased in the spleen
|
|
• at 20 weeks after pIpC induction, liver shows extramedullary hematopoiesis with highly atypical megakaryocytes, but islands with myelopoeisis and erythropoiesis can also be found
• at 20 weeks after pIpC induction, hematopoietic cells, including megakaryocytes are seen in the lung
• at 20 weeks after pIpC induction, colony assays of progenitors show extramedullary hematopoiesis with markedly increased erythroid and myeloid progenitor numbers in spleen
|
|
• at 20 weeks after pIpC induction, bone marrow shows hypercellularity with trilineage hyperplasia
|
|
• at 20 weeks after pIpC induction, an increase in numbers of megakaryocytes in the spleen and bone marrow is seen at 20 weeks of age, most with morphological abnormalities such as hyperchromatic, hyperlobulated nuclei, and bizarre nuclear configuration, and often forming clusters
|
|
• at 20 weeks after pIpC induction, colony assays of progenitors show extramedullary hematopoiesis with markedly increased erythroid and myeloid progenitor numbers in spleen
|
|
• at 20 weeks after pIpC induction, collagen-based culture indicates a massive expansion of CFU-MK in the spleen
|
|
• at 10 weeks after pIpC induction, mutants exhibit an increase in erythrocyte numbers
|
|
• at 10 weeks after pIpC induction, mutants exhibit elevated hemoglobin
|
|
• at 10 weeks after pIpC induction, mutants exhibit a slight decrease in mean corpuscular volume
|
|
• at 10 weeks after pIpC induction, mutants exhibit neutrophilia
|
|
• at 10 weeks after pIpC induction, mutants exhibit thrombocytosis
|
|
• at 20 weeks after pIpC induction, the relative amount of B and T cells in the spleen and bone marrow is reduced
|
|
• at 20 weeks after pIpC induction, the relative amount of B and T cells in the spleen and bone marrow is reduced
|
|
• at 20 weeks after pIpC induction, destruction of normal splenic architecture by atypical hematopoiesis is seen in some sections of the spleen
|
|
• splenomegaly is seen after pIpC induction
|
|
• spleen fibrosis is seen at 20 weeks after pIpC induction
|
|
• at 20 weeks after pIpC induction, myeloid cells are the predominant cell population in the bone marrow and are increased in the spleen
|
|
• at 10 weeks after pIpC induction, mutants exhibit neutrophilia
|
|
• at 20 weeks after pIpC induction, the relative amount of B and T cells in the spleen and bone marrow is reduced
|
|
• at 20 weeks after pIpC induction, the relative amount of B and T cells in the spleen and bone marrow is reduced
|
|
• at 20 weeks after pIpC induction, destruction of normal splenic architecture by atypical hematopoiesis is seen in some sections of the spleen
|
|
• splenomegaly is seen after pIpC induction
|
|
• spleen fibrosis is seen at 20 weeks after pIpC induction
|
|
• bone marrow fibrosis is seen at 20 weeks after pIpC induction
|
|
• splenomegaly is seen after pIpC induction
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| polycythemia vera | DOID:8997 |
OMIM:263300 |
J:134364 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die within 2 weeks of pIpC treatment
• however, transplantation with wild-type bone marrow rescues lethality
|
|
• pIpC-treated mice exhibit reduced GM- and GEMM-CFUs compared with control mice
|
|
• pIpC-treated mice exhibit spots of proliferating lymphoid cells unlike in control mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit reduced Lin-Sca-Kit+ cells compared with control mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased leukocyte apoptosis in bone marrow unlike control mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit spots of proliferating lymphoid cells unlike in control mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal survival
|
| N |
• pIpC-treated mice exhibit normal hematological parameters
• CFU-GM cells from pIpC-treated mice exhibit normal cytokine response
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• some pIpC-treated mice die prematurely from T lineage acute lymphoblastic leukemia
|
|
• marked splenomegaly 2 days after pIpC induction
(J:174880)
• in pIpC-treated mice
(J:204263)
|
|
• cells from pIpC-treated mice exhibit cytokine-independent CFU-GM growth and pronounced GM-CSF hypersensitivity compared with control cells
|
|
• display a myeloproliferative phenotype 2 days after pIpC induction
|
|
• all pIpC-treated mice exhibit overt myeloproliferative neoplasm
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• some pIpC-treated mice die prematurely from T lineage acute lymphoblastic leukemia
|
|
• marked splenomegaly 2 days after pIpC induction
(J:174880)
• in pIpC-treated mice
(J:204263)
|
|
• display a myeloproliferative phenotype 2 days after pIpC induction
|
|
• all pIpC-treated mice exhibit overt myeloproliferative neoplasm
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• marked splenomegaly 2 days after pIpC induction
(J:174880)
• in pIpC-treated mice
(J:204263)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• the IgM+HSAhigh immature B cell compartment in the spleen is absent two weeks after induction of Cre expression in mice 8-10 weeks old
|
|
• B cell development is arrested at the pro-B cell stage two weeks after induction of Cre expression in mice 8-10 weeks old
|
|
• T cell development is arrested at the pro-T cell stage two weeks after induction of Cre expression in mice 8-10 weeks old
|
|
• the number of mature B cells in the bone marrow drop by half within two weeks of induction of Cre expression in mice 8-10 weeks old and then decline slowly over the next year with a half-life of 156 days
• the number of mature B cells in the spleen is reduced by 67% two weeks after Cre induction
• mature B cell numbers are reduced to 32% in the spleen 17 weeks after Cre induction and remain at this level for at least one year
• mature B cell numbers in lymph nodes drop to 58% of normal 10 weeks after Cre induction, and continue to drop to 11% of normal 17 weeks after Cre induction
• mature B cell numbers remain at 11% of normal between 17 and 54 weeks after induction of Cre expression
• when Cre is induced in neonates, mature B cells numbers are 10- to 30- fold below normal
|
|
• the number of follicular B cells in the spleen decline slowly after induction of Cre expression in mice 8-10 weeks old with a half-life of 134 days
|
|
• marginal zone B cells are decreased in number by 75% when Cre-induction occurs at birth
• the number of marginal zone B cells increases slightly with age but remains well below normal levels
• marginal zone B cell numbers are normal when Cre-induction occurs in mice 8 to 10 weeks of age
|
|
• the total number of IgM secreting plasma cells found in the spleen is 3- to 4- fold larger in mice where Cre induction is induced at birth than in controls
|
|
• pre-B cells are absent in the bone marrow of mice two weeks after induction of Cre expression in mice 8-10 weeks old
|
|
• peripheral B cells have an activated phenotype in mice that have Cre expression induced at birth
• the activated phenotype include larger cell size and increased expression of CD25, CD69, CD86 and MHC-II when analyzed at 8 weeks of age
• B cells do not have this activated phenotype when Cre is induced in mice 8-10 weeks of age
|
|
• the IgM+HSAhigh immature B cell compartment in the spleen is absent two weeks after induction of Cre expression in mice 8-10 weeks old
|
|
• B cell development is arrested at the pro-B cell stage two weeks after induction of Cre expression in mice 8-10 weeks old
|
|
• T cell development is arrested at the pro-T cell stage two weeks after induction of Cre expression in mice 8-10 weeks old
|
|
• the number of mature B cells in the bone marrow drop by half within two weeks of induction of Cre expression in mice 8-10 weeks old and then decline slowly over the next year with a half-life of 156 days
• the number of mature B cells in the spleen is reduced by 67% two weeks after Cre induction
• mature B cell numbers are reduced to 32% in the spleen 17 weeks after Cre induction and remain at this level for at least one year
• mature B cell numbers in lymph nodes drop to 58% of normal 10 weeks after Cre induction, and continue to drop to 11% of normal 17 weeks after Cre induction
• mature B cell numbers remain at 11% of normal between 17 and 54 weeks after induction of Cre expression
• when Cre is induced in neonates, mature B cells numbers are 10- to 30- fold below normal
|
|
• the number of follicular B cells in the spleen decline slowly after induction of Cre expression in mice 8-10 weeks old with a half-life of 134 days
|
|
• marginal zone B cells are decreased in number by 75% when Cre-induction occurs at birth
• the number of marginal zone B cells increases slightly with age but remains well below normal levels
• marginal zone B cell numbers are normal when Cre-induction occurs in mice 8 to 10 weeks of age
|
|
• the total number of IgM secreting plasma cells found in the spleen is 3- to 4- fold larger in mice where Cre induction is induced at birth than in controls
|
|
• pre-B cells are absent in the bone marrow of mice two weeks after induction of Cre expression in mice 8-10 weeks old
|
|
• peripheral B cells have an activated phenotype in mice that have Cre expression induced at birth
• the activated phenotype include larger cell size and increased expression of CD25, CD69, CD86 and MHC-II when analyzed at 8 weeks of age
• B cells do not have this activated phenotype when Cre is induced in mice 8-10 weeks of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 1 pIpC treated mouse was euthanized due to severe disease at 12 weeks of age
|
|
• in mice with intestinal inflammation
|
|
• diarrhea with bloody feces is seen in mice with intestinal inflammation
|
|
• in a few mice, regardless of pIpC treatment
|
|
• in mice with leukemia
|
|
• most of the mast cells in pIpC treated mice with mastocytosis are round with some degree of hypergranulation and only few spindle shaped cells are seen
|
|
• mice treated with 3 injections of pIpC every second day at 4 to 10 weeks of age develop diffuse mastocytosis by 13 - 38 weeks of age
• pIpC treated mice display a variable increase in cutaneous mast cell numbers
• in some pIpC treated mice accumulations of mast cells are seen in the lymph nodes
• mice not treated with pIpC develop phenotypes similar to those in pIpC injected mice
|
|
• bone marrow cells are unable to engraft in nonirradiated recipient mice
|
|
• some pIpC treated mice develop large numbers of dermal mast cell tumors of variable size
• in a few mice these tumors are macroscopically visible
• mice not treated with pIpC develop phenotypes similar to those in pIpC injected mice
|
|
• some mice, regardless of pIpC treatment, develop a condition resembling B-lymphoblastic leukemia
|
|
• in mice with intestinal inflammation
|
|
• in mice with leukemia
|
|
• some pIpC treated mice develop large numbers of dermal mast cell tumors of variable size
• in a few mice these tumors are macroscopically visible
• mice not treated with pIpC develop phenotypes similar to those in pIpC injected mice
|
|
• in a few mice, regardless of pIpC treatment
|
|
• in mice with leukemia
|
|
• most of the mast cells in pIpC treated mice with mastocytosis are round with some degree of hypergranulation and only few spindle shaped cells are seen
|
|
• mice treated with 3 injections of pIpC every second day at 4 to 10 weeks of age develop diffuse mastocytosis by 13 - 38 weeks of age
• pIpC treated mice display a variable increase in cutaneous mast cell numbers
• in some pIpC treated mice accumulations of mast cells are seen in the lymph nodes
• mice not treated with pIpC develop phenotypes similar to those in pIpC injected mice
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| mastocytosis | DOID:350 |
OMIM:154800 |
J:169611 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• numerous neutrophilic crypt abscesses are detected in several mice with intestinal inflammation
|
|
• inflammation results in extensive destruction of the mucosa with crypts separated from each other and from the lamina muscularis propria by the infiltrating cells
• outside of inflammatory lesions the colonic mucosa appears normal with the exception of an increase in mast cell numbers
|
|
• in mice with intestinal inflammation
|
|
• diarrhea with bloody feces is seen in mice with intestinal inflammation
|
|
• in all mice, regardless of pIpC treatment
• severity of inflammation varies and severe inflammation is more common in older mice
• inflammatory changes affect sharply demarcated patches of the mucosa and in most mice occur in long stretches of the mucosa
• most lesions are found in the cecum and ascending colon
• lesions are characterized by a massive infiltration of T cells, B cells, macrophages, and neutrophils with high numbers of mast cells found in the crypt epithelium surrounding the lesion
• the surface epithelium shows erosions in several mice
|
|
• in a few mice, regardless of pIpC treatment
|
|
• most of the mast cells in pIpC treated mice with mastocytosis are round with some degree of hypergranulation and only few spindle shaped cells are seen
|
|
• mice treated with 3 injections of pIpC every second day at 4 to 10 weeks of age develop diffuse mastocytosis by 13 - 38 weeks of age
• pIpC treated mice display a variable increase in cutaneous mast cell numbers
• in some pIpC treated mice accumulations of mast cells are seen in the lymph nodes, spleen, liver and/or stomach
• mice not treated with pIpC develop phenotypes similar to those in pIpC injected mice
|
|
• bone marrow cells are unable to engraft in nonirradiated recipient mice
|
|
• some pIpC treated mice develop large numbers of dermal mast cell tumors of variable size
• in a few mice these tumors are macroscopically visible
• mice not treated with pIpC develop phenotypes similar to those in pIpC injected mice
|
|
• in mice with intestinal inflammation
|
|
• some pIpC treated mice develop large numbers of dermal mast cell tumors of variable size
• in a few mice these tumors are macroscopically visible
• mice not treated with pIpC develop phenotypes similar to those in pIpC injected mice
|
|
• in all mice, regardless of pIpC treatment
• severity of inflammation varies and severe inflammation is more common in older mice
• inflammatory changes affect sharply demarcated patches of the mucosa and in most mice occur in long stretches of the mucosa
• most lesions are found in the cecum and ascending colon
• lesions are characterized by a massive infiltration of T cells, B cells, macrophages, and neutrophils with high numbers of mast cells found in the crypt epithelium surrounding the lesion
• the surface epithelium shows erosions in several mice
|
|
• in a few mice, regardless of pIpC treatment
|
|
• most of the mast cells in pIpC treated mice with mastocytosis are round with some degree of hypergranulation and only few spindle shaped cells are seen
|
|
• mice treated with 3 injections of pIpC every second day at 4 to 10 weeks of age develop diffuse mastocytosis by 13 - 38 weeks of age
• pIpC treated mice display a variable increase in cutaneous mast cell numbers
• in some pIpC treated mice accumulations of mast cells are seen in the lymph nodes, spleen, liver and/or stomach
• mice not treated with pIpC develop phenotypes similar to those in pIpC injected mice
|
|
• numerous neutrophilic crypt abscesses are detected in several mice with intestinal inflammation
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| mastocytosis | DOID:350 |
OMIM:154800 |
J:169611 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• some mice, regardless of pIpC treatment, die or are euthanized due to severe disease between 15 and 35 weeks of age
|
|
• numerous neutrophilic crypt abscesses are detected in several mice with intestinal inflammation
|
|
• inflammation results in extensive destruction of the mucosa with crypts separated from each other and from the lamina muscularis propria by the infiltrating cells
• outside of inflammatory lesions the colonic mucosa appears normal with the exception of an increase in mast cell numbers
|
|
• in mice with intestinal inflammation
|
|
• diarrhea with bloody feces is seen in mice with intestinal inflammation
|
|
• in all mice, regardless of pIpC treatment
• severity of inflammation varies and severe inflammation is more common in older mice
• inflammatory changes affect sharply demarcated patches of the mucosa and in most mice occur in long stretches of the mucosa
• most lesions are found in the cecum and ascending colon
• lesions are characterized by a massive infiltration of T cells, B cells, macrophages, and neutrophils with high numbers of mast cells found in the crypt epithelium surrounding the lesion
• the surface epithelium shows erosions in several mice
|
|
• in a few mice, regardless of pIpC treatment
|
|
• in mice with leukemia
|
|
• most of the mast cells in pIpC treated mice with mastocytosis are round with some degree of hypergranulation and only few spindle shaped cells are seen
|
|
• mice treated with 3 injections of pIpC every second day at 4 to 10 weeks of age develop diffuse mastocytosis by 13 - 38 weeks of age
• pIpC treated mice display a variable increase in cutaneous mast cell numbers
• in some pIpC treated mice accumulations of mast cells are seen in the lymph nodes and/or spleen
• mice not treated with pIpC develop phenotypes similar to those in pIpC injected mice
|
|
• bone marrow cells are unable to engraft in nonirradiated recipient mice
|
|
• some pIpC treated mice develop large numbers of dermal mast cell tumors of variable size
• in a few mice these tumors are macroscopically visible
• mice not treated with pIpC develop phenotypes similar to those in pIpC injected mice
|
|
• some mice, regardless of pIpC treatment, develop a condition resembling B-lymphoblastic leukemia
|
|
• in 1 pIpC treated mouse
|
|
• in mice with intestinal inflammation
|
|
• in mice with leukemia
|
|
• some pIpC treated mice develop large numbers of dermal mast cell tumors of variable size
• in a few mice these tumors are macroscopically visible
• mice not treated with pIpC develop phenotypes similar to those in pIpC injected mice
|
|
• in all mice, regardless of pIpC treatment
• severity of inflammation varies and severe inflammation is more common in older mice
• inflammatory changes affect sharply demarcated patches of the mucosa and in most mice occur in long stretches of the mucosa
• most lesions are found in the cecum and ascending colon
• lesions are characterized by a massive infiltration of T cells, B cells, macrophages, and neutrophils with high numbers of mast cells found in the crypt epithelium surrounding the lesion
• the surface epithelium shows erosions in several mice
|
|
• in a few mice, regardless of pIpC treatment
|
|
• in mice with leukemia
|
|
• most of the mast cells in pIpC treated mice with mastocytosis are round with some degree of hypergranulation and only few spindle shaped cells are seen
|
|
• mice treated with 3 injections of pIpC every second day at 4 to 10 weeks of age develop diffuse mastocytosis by 13 - 38 weeks of age
• pIpC treated mice display a variable increase in cutaneous mast cell numbers
• in some pIpC treated mice accumulations of mast cells are seen in the lymph nodes and/or spleen
• mice not treated with pIpC develop phenotypes similar to those in pIpC injected mice
|
|
• numerous neutrophilic crypt abscesses are detected in several mice with intestinal inflammation
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| mastocytosis | DOID:350 |
OMIM:154800 |
J:169611 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• normal hematopoietic stem cell maintenance and self-renewal in steady state homeostasis as well as under stringent challenge situations
• normal development of splenic marginal zone B cells when tested in competitive mixed bone marrow chimeras
|
|
• reduced total, DP, CD4 SP and CD8 SP cell numbers in the thymus when tested in competitive mixed bone marrow chimeras
• dramatic failure of bone marrow progenitors to contribute to thymus cellularity (total and DP) in competitive mixed bone marrow chimeras
• normal thymic B cells
• normal cell death and proliferative capacity
|
|
• increased immature B cells after competitive intrathymic transfer
|
|
• intrathymicly transferred Lin- bone marrow progenitors develop into T cells with markedly slower kinetics compared to control cells
• failure of Lin- bone marrow progenitors to contribute to thymus cellularity at 16 days after competitive intrathymic transfer
• normal percentage of DN, DP, CD4+, and CD8+ SP thymocyte subpopulations at 21 days after transfer
|
|
• reduced absolute cell numbers when tested in competitive mixed bone marrow chimeras
|
|
• reduced absolute cell numbers when tested in competitive mixed bone marrow chimeras
|
|
• reduced absolute cell numbers when tested in competitive mixed bone marrow chimeras
|
|
• reduced absolute cell numbers when tested in competitive mixed bone marrow chimeras
|
|
• increased relative numbers of DN1 compared to the corresponding control at 16 days after intrathymic transfer of Lin- bone marrow progenitors
|
|
• reduced numbers of DP thymocytes after competitive intrathymic transfer
|
|
• reduced frequency and absolute numbers of gamma-delta T cells when tested in competitive mixed bone marrow chimeras
|
|
• reduced total, DP, CD4 SP and CD8 SP cell numbers in the thymus when tested in competitive mixed bone marrow chimeras
• dramatic failure of bone marrow progenitors to contribute to thymus cellularity (total and DP) in competitive mixed bone marrow chimeras
• normal thymic B cells
• normal cell death and proliferative capacity
|
|
• increased immature B cells after competitive intrathymic transfer
|
|
• intrathymicly transferred Lin- bone marrow progenitors develop into T cells with markedly slower kinetics compared to control cells
• failure of Lin- bone marrow progenitors to contribute to thymus cellularity at 16 days after competitive intrathymic transfer
• normal percentage of DN, DP, CD4+, and CD8+ SP thymocyte subpopulations at 21 days after transfer
|
|
• reduced absolute cell numbers when tested in competitive mixed bone marrow chimeras
|
|
• reduced absolute cell numbers when tested in competitive mixed bone marrow chimeras
|
|
• reduced absolute cell numbers when tested in competitive mixed bone marrow chimeras
|
|
• reduced absolute cell numbers when tested in competitive mixed bone marrow chimeras
|
|
• increased relative numbers of DN1 compared to the corresponding control at 16 days after intrathymic transfer of Lin- bone marrow progenitors
|
|
• reduced numbers of DP thymocytes after competitive intrathymic transfer
|
|
• reduced frequency and absolute numbers of gamma-delta T cells when tested in competitive mixed bone marrow chimeras
|
|
• reduced total, DP, CD4 SP and CD8 SP cell numbers in the thymus when tested in competitive mixed bone marrow chimeras
• dramatic failure of bone marrow progenitors to contribute to thymus cellularity (total and DP) in competitive mixed bone marrow chimeras
• normal thymic B cells
• normal cell death and proliferative capacity
|
|
• reduced absolute cell numbers when tested in competitive mixed bone marrow chimeras
|
|
• reduced absolute cell numbers when tested in competitive mixed bone marrow chimeras
|
|
• reduced absolute cell numbers when tested in competitive mixed bone marrow chimeras
|
|
• reduced absolute cell numbers when tested in competitive mixed bone marrow chimeras
|
|
• increased relative numbers of DN1 compared to the corresponding control at 16 days after intrathymic transfer of Lin- bone marrow progenitors
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pI-pC injected mice show an increase in hepatic stellate cell activation (as indicated by increased alpha-smooth muscle cell actin levels) and elevated production of latent TGF-beta complexes following acute liver injury induced with CCl4, however collagen network formation is normal after injury
|
|
• pI-pC injected mice show an increase in hepatic stellate cell activation (as indicated by increased alpha-smooth muscle cell actin levels) and elevated production of latent TGF-beta complexes following acute liver injury induced with carbon tetrachloride (CCl4), however collagen network formation is normal after injury
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• thymi in pIpC-treated mice exhibit a greater than 10-fold increase in MHCII+ (IA/IE) and B220+ (CD45R) cells compared with wild-type mice
|
|
• up to 8-fold in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased cells positive for CD69 and CD44 compared with wild-type mice
• T cell maturation in pIpC-treated mice is impaired compared to in wild-type mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased serum levels of IL1b, IL1a, IL2, IL3, IL6, IL9, IL10, IL13, Ccl2, Ccl3, Ccl4, TNF-alpha, GM-CSF (granulocyte-macrophage colony-stimulating factor), and IFN-gamma compared with wild-type mice
|
|
• pIpC-treated mice exhibit decreased MIP-1alpha (Ccl3), MCP-1 (Ccl2), and MIP-1beta (Ccl4) serum levels compared with wild-type mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• osteoblast differentiation of stromal cells from pIpC-treated mice is reduced compared to for wild-type cells
• in vivo osteoblast differentiation in pIpC-treated mice is reduced compared to in wild-type mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit reduced trabecular bone volume with increased trabecular space compared with wild-type mice
|
|
• pIpC-treated mice exhibit avascular osteonecrosis unlike wild-type mice
|
|
• at 14 months of age, pIpC-treated mice exhibit reduced bone formation compared with wild-type mice
• however, bone formation rate is normal at 3 months of age in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• up to 8-fold in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased serum levels of IL1b, IL1a, IL2, IL3, IL6, IL9, IL10, IL13, Ccl2, Ccl3, Ccl4, TNF-alpha, GM-CSF (granulocyte-macrophage colony-stimulating factor), and IFN-gamma compared with wild-type mice
|
|
• pIpC-treated mice exhibit decreased MIP-1alpha (Ccl3), MCP-1 (Ccl2), and MIP-1beta (Ccl4) serum levels compared with wild-type mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• thymi in pIpC-treated mice exhibit a greater than 10-fold increase in MHCII+ (IA/IE) and B220+ (CD45R) cells compared with wild-type mice
|
|
• up to 8-fold in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased cells positive for CD69 and CD44 compared with wild-type mice
• T cell maturation in pIpC-treated mice is impaired compared to in wild-type mice
|
|
• in pIpC-treated mice
|
|
• in the spleen and liver of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• osteoblast differentiation of stromal cells from pIpC-treated mice is reduced compared to for wild-type cells
• in vivo osteoblast differentiation in pIpC-treated mice is reduced compared to in wild-type mice
|
|
• thymi in pIpC-treated mice exhibit a greater than 10-fold increase in MHCII+ (IA/IE) and B220+ (CD45R) cells compared with wild-type mice
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Gaucher's disease type I | DOID:0110957 |
OMIM:230800 |
J:167081 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• thymi in pIpC-treated mice exhibit a greater than 10-fold increase in MHCII+ (IA/IE) and B220+ (CD45R) cells compared with wild-type mice
|
|
• up to 8-fold in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased cells positive for CD69 and CD44 compared with wild-type mice
• T cell maturation in pIpC-treated mice is impaired compared to in wild-type mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased serum levels of IL1b, IL1a, IL2, IL3, IL6, IL9, IL10, IL13, Ccl2, Ccl3, Ccl4, TNF-alpha, GM-CSF (granulocyte-macrophage colony-stimulating factor), and IFN-gamma compared with wild-type mice
|
|
• pIpC-treated mice exhibit decreased MIP-1alpha (Ccl3), MCP-1 (Ccl2), and MIP-1beta (Ccl4) serum levels compared with wild-type mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• osteoblast differentiation of stromal cells from pIpC-treated mice is reduced compared to for wild-type cells
• in vivo osteoblast differentiation in pIpC-treated mice is reduced compared to in wild-type mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit reduced trabecular bone volume with increased trabecular space compared with wild-type mice
|
|
• pIpC-treated mice exhibit avascular osteonecrosis unlike wild-type mice
|
|
• at 14 months of age, pIpC-treated mice exhibit reduced bone formation compared with wild-type mice
• however, bone formation rate is normal at 3 months of age in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• up to 8-fold in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased serum levels of IL1b, IL1a, IL2, IL3, IL6, IL9, IL10, IL13, Ccl2, Ccl3, Ccl4, TNF-alpha, GM-CSF (granulocyte-macrophage colony-stimulating factor), and IFN-gamma compared with wild-type mice
|
|
• pIpC-treated mice exhibit decreased MIP-1alpha (Ccl3), MCP-1 (Ccl2), and MIP-1beta (Ccl4) serum levels compared with wild-type mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• thymi in pIpC-treated mice exhibit a greater than 10-fold increase in MHCII+ (IA/IE) and B220+ (CD45R) cells compared with wild-type mice
|
|
• up to 8-fold in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased cells positive for CD69 and CD44 compared with wild-type mice
• T cell maturation in pIpC-treated mice is impaired compared to in wild-type mice
|
|
• in pIpC-treated mice
|
|
• in the spleen and liver of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• osteoblast differentiation of stromal cells from pIpC-treated mice is reduced compared to for wild-type cells
• in vivo osteoblast differentiation in pIpC-treated mice is reduced compared to in wild-type mice
|
|
• thymi in pIpC-treated mice exhibit a greater than 10-fold increase in MHCII+ (IA/IE) and B220+ (CD45R) cells compared with wild-type mice
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Gaucher's disease type I | DOID:0110957 |
OMIM:230800 |
J:167081 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• the percent GFP+ cells in irradiated tamoxifen-treated mice reconstituted with irradiated lymphocyte and HSPC compartments is greater than in mice reconstituted with only the lymphocyte compartment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased thymic apoptosis compared with Srrttm1.1Thsn/Srrttm1.2Thsn control mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased thymic apoptosis compared with Srrttm1.1Thsn/Srrttm1.2Thsn control mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased thymic apoptosis compared with Srrttm1.1Thsn/Srrttm1.2Thsn control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• macrophges from mice where cre recombinase expression was induced produce less reactive NO in response to IFN-gamma, and to combinations of TNF/IFN-gamma, TNF/LPS or IFN-gamma/LPS
• similar results are obtained with TLR2, TLR3 and TLR9 agonists
|
|
• macrophges from mice where cre recombinase expression was induced produce less reactive NO in response to IFN-gamma, and to combinations of TNF/IFN-gamma, TNF/LPS or IFN-gamma/LPS
• similar results are obtained with TLR2, TLR3 and TLR9 agonists
|
|
• macrophges from mice where cre recombinase expression was induced produce less reactive NO in response to IFN-gamma, and to combinations of TNF/IFN-gamma, TNF/LPS or IFN-gamma/LPS
• similar results are obtained with TLR2, TLR3 and TLR9 agonists
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• platelets have delayed recovery of numbers after administration of Fluorouracil
|
|
• platelet cell number is moderately decreased compared to controls 4 weeks after cre induction
|
|
• bone marrow HSC have reduced proliferation relative to controls when cultured in vitro
• both accelerated apoptosis and impaired cell cycling occur in these cells
• increased rates of apoptosis are observed in vivo in the fetal liver after cre induction
|
|
• HSC and CFU numbers in the bone marrow significantly decrease after cre induction
• 12 weeks after induction, HSC numbers have recovered but consist entirely of HSC that have escaped cre-mediated excision of the gene locus
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• after cre induction, osteoclasts fail to develop from bone marrow cells in response to culturing with either osteoblasts, RANKL or M-CSF
• normal numbers of osteoclast progenitors are present in the bone marrow suggesting a defect in differentiation
|
|
• some mice have overgrowth of the upper incisors with short or absent lower incisors
|
|
• some mice have overgrowth of the upper incisors with short or absent lower incisors
|
|
• some mice have overgrowth of the upper incisors with short or absent lower incisors
|
|
• lower mandible has a marked retention of hypertrophic cartilage when cre is induced at 10 days of age
|
|
• the number of osteoclasts per mm bone surface is severely reduced in mice with cre induction at 10 days of age
|
|
• cre induction at 10 days of age leads to growth plate dysplasia, characterized by an increase in thickness, acellular areas, and the retention of hypertrophic chondrocytes beyond the chondro-osseous junction
|
|
• cre-induction at 10 days of age leads to shortened long bones by 5 months of age
|
|
• cre induction at 10 days of age leads to short, club-shaped femurs, with higher radiodensity at the distal portion
|
|
• cre induction at 10 days of age leads to short, club-shaped tibias, with higher radiodensity at the proximal portion
|
|
• the bone volume to total volume fraction of femurs is twice that of controls when cre is induced at 10 days of age
• cre induction at 10 days of age also leads to other features of severe osteopetrosis, including improperly shaped long bones, and a failure to resorb calcified cartilage resulting in aberrant endochondral growth and ossification
|
|
• cre induction at 10 days of age leads to a massive increase in calcified cartilage adjacent to the growth plates
|
|
• some mice have overgrowth of the upper incisors with short or absent lower incisors
|
|
• some mice have overgrowth of the upper incisors with short or absent lower incisors
|
|
• some mice have overgrowth of the upper incisors with short or absent lower incisors
|
|
• lower mandible has a marked retention of hypertrophic cartilage when cre is induced at 10 days of age
|
|
• cre induction at 10 days of age leads to short, club-shaped femurs, with higher radiodensity at the distal portion
|
|
• cre induction at 10 days of age leads to short, club-shaped tibias, with higher radiodensity at the proximal portion
|
|
• after cre induction, osteoclasts fail to develop from bone marrow cells in response to culturing with either osteoblasts, RANKL or M-CSF
• normal numbers of osteoclast progenitors are present in the bone marrow suggesting a defect in differentiation
|
|
• the number of osteoclasts per mm bone surface is severely reduced in mice with cre induction at 10 days of age
|
|
• after cre induction, osteoclasts fail to develop from bone marrow cells in response to culturing with either osteoblasts, RANKL or M-CSF
• normal numbers of osteoclast progenitors are present in the bone marrow suggesting a defect in differentiation
|
|
• the number of osteoclasts per mm bone surface is severely reduced in mice with cre induction at 10 days of age
|
|
• after cre induction, osteoclasts fail to develop from bone marrow cells in response to culturing with either osteoblasts, RANKL or M-CSF
• normal numbers of osteoclast progenitors are present in the bone marrow suggesting a defect in differentiation
|
|
• some mice have overgrowth of the upper incisors with short or absent lower incisors
|
|
• some mice have overgrowth of the upper incisors with short or absent lower incisors
|
|
• some mice have overgrowth of the upper incisors with short or absent lower incisors
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following treatment with poly(I)/poly(C), B cell numbers are decreased by up to 70% of wild-type numbers in the red pulp of the spleen
|
|
• following treatment with poly(I)/poly(C), marginal metallophilic macrophages are decreased in number in areas where B cell numbers are reduced
|
|
• following treatment with poly(I)/poly(C), marginal zone metallophilic macrophages are decreased in number in areas where B cell numbers are reduced
|
|
• following treatment with poly(I)/poly(C), B cell numbers are decreased by up to 70% of wild-type numbers in the red pulp of the spleen
• following treatment with poly(I)/poly(C), follicles are reduced in size
|
|
• following treatment with poly(I)/poly(C), B cell numbers are decreased by up to 70% of wild-type numbers in the red pulp of the spleen
|
|
• following treatment with poly(I)/poly(C), marginal metallophilic macrophages are decreased in number in areas where B cell numbers are reduced
|
|
• following treatment with poly(I)/poly(C), marginal zone metallophilic macrophages are decreased in number in areas where B cell numbers are reduced
|
|
• following treatment with poly(I)/poly(C), B cell numbers are decreased by up to 70% of wild-type numbers in the red pulp of the spleen
• following treatment with poly(I)/poly(C), follicles are reduced in size
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• pIpC-treated mice exhibit normal liver and bone marrow
|
| N |
• pIpC-treated mice exhibit normal liver and bone marrow
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Increased bone mass in polyI:C treated Slc4a2tm2Ges/Slc4a2tm2Ges Tg(Mx1-cre)1Cgn/0 mice
|
• enlarged following polyI:C treatment
|
|
• impaired attachment to bone surfaces following polyI:C treatment
• abnormal spreading and reduced calpain activity in vitro following polyI:C treatment
|
|
• following polyI:C treatment
|
|
• enlarged following polyI:C treatment
|
|
• impaired attachment to bone surfaces following polyI:C treatment
• abnormal spreading and reduced calpain activity in vitro following polyI:C treatment
|
|
• enlarged following polyI:C treatment
|
|
• impaired attachment to bone surfaces following polyI:C treatment
• abnormal spreading and reduced calpain activity in vitro following polyI:C treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pIpC-treated mice phenocopy abnormalities observed in Ccnd3tm1Pisc homozygotes
|
|
• in pIpC-treated mice
|
|
• modest in pIpC-treated mice
|
|
• modest in pIpC-treated mice
|
|
• in the thymus of pIpC-treated mice
|
|
• hematopoietic progenitor cells transduced with a retrovirus encoding activated Notch1 and injected into irradiated C57BL/6 mice induce apoptosis in acute lymphoblastic leukemia cells following pIpC-treatment compared with control mice
|
|
• in pIpC-treated mice
|
|
• modest in pIpC-treated mice
|
|
• in the thymus of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• pIpC-treated mice exhibit normal T cell development
|
|
• 2-fold in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in the bone marrow of pIpC-treated mice
• 2-fold in the spleen of pIpC-treated mice
|
|
• in the bone marrow of pIpC-treated mice
|
|
• modest in pIpC-treated mice
|
|
• 2-fold in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in the bone marrow of pIpC-treated mice
• 2-fold in the spleen of pIpC-treated mice
|
|
• in the bone marrow of pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• expansion of immature megakaryocytes and blocked differentiation in pIpC-treated mice
|
|
• mild in pIpC-treated mice
|
|
• in the bone marrow and spleen of pIpC-treated mice
|
|
• 2-fold in the bone marrow in pIpC-treated mice
|
|
• larger in size in pIpC-treated mice compared to in control mice
|
|
• in pIpC-treated mice
|
|
• expansion of immature megakaryocytes and blocked differentiation in pIpC-treated mice
|
|
• mild in pIpC-treated mice
|
|
• in the bone marrow and spleen of pIpC-treated mice
|
|
• mild in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• expansion of immature megakaryocytes and blocked differentiation in pIpC-treated mice
|
|
• expansion of immature megakaryocytes and blocked differentiation in pIpC-treated mice
|
|
• mild in pIpC-treated mice
|
|
• 4-fold in the bone marrow in pIpC-treated mice
|
|
• larger in size in pIpC-treated mice compared to in control mice
|
|
• in pIpC-treated mice
|
|
• mild in pIpC-treated mice
|
|
• mild in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal red blood cell numbers and hemoglobin content
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• increased Gr-1/Mac-1+ cells in the spleen of pIpC-treated mice
|
|
• increased myeloid, megakaryocyte/erythroid and granulocyte/macrophage progenitors in the bone marrow and spleen of pIpC-treated mice
• increased granulocyte-macrophage progenitors in the spleen of pIpC-treated mice
|
|
• increased myeloid progenitors in the spleen of pIpC-treated mice
|
|
• in pIpC-treated mice with trilineage hyperplasia
|
|
• in pIpC-treated mice with increased number of megakaryocytes and clusters of immature erythroid precursors
|
|
• in the splenic red pulp of pIpC-treated mice
• 20-fold increase in CD71/Ter-119+ cells in the spleen of pIpC-treated mice
• in the bone marrow and spleen of pIpC-treated mice
|
|
• in pIpC-treated mice within 4 weeks and sustained for more than 20 weeks
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice within 4 weeks and sustained for more than 20 weeks
|
|
• in pIpC-treated mice within 4 weeks and sustained for more than 20 weeks
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in the bone marrow and spleen of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in the bone marrow and spleen of pIpC-treated mice
|
|
• reticulin fibrosis in pIpC-treated mice
|
|
• in pIpC-treated mice with increased number of megakaryocytes and clusters of immature erythroid precursors
|
|
• fibrosis in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• fibrosis in the splenic red and white pulp of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• increased Gr-1/Mac-1+ cells in the spleen of pIpC-treated mice
|
|
• in the bone marrow and spleen of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• reticulin fibrosis in pIpC-treated mice
|
|
• in pIpC-treated mice with increased number of megakaryocytes and clusters of immature erythroid precursors
|
|
• fibrosis in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• fibrosis in the splenic red and white pulp of pIpC-treated mice
|
|
• fibrosis in pIpC-treated mice
|
|
• fibrosis in the bone marrow cavity of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| polycythemia vera | DOID:8997 |
OMIM:263300 |
J:183821 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• intermediate in pIpC-treated mice
|
|
• intermediate in pIpC-treated mice
|
|
• increased Gr-1/Mac-1+ cells in the spleen of pIpC-treated mice
|
|
• intermediate increased myeloid, megakaryocyte/erythroid and granulocyte/macrophage progenitors in the bone marrow and spleen of pIpC-treated mice
• increased granulocyte-macrophage progenitors in the spleen of pIpC-treated mice
|
|
• increased myeloid progenitors in the spleen of pIpC-treated mice
|
|
• in the splenic red pulp of pIpC-treated mice
|
|
• in the splenic red pulp of pIpC-treated mice
• 10-fold increase in CD71/Ter-119+ cells in the spleen of pIpC-treated mice
• intermediate in the bone marrow and spleen of pIpC-treated mice
|
|
• intermediate in pIpC-treated mice within 4 weeks and sustained for more than 20 weeks
|
|
• intermediate in pIpC-treated mice
|
|
• in pIpC-treated mice within 4 weeks and sustained for more than 20 weeks
|
|
• in pIpC-treated mice within 4 weeks and sustained for more than 20 weeks
|
|
• in pIpC-treated mice
|
|
• intermediate in pIpC-treated mice
|
|
• in the bone marrow and spleen of pIpC-treated mice
|
|
• intermediate in pIpC-treated mice
|
|
• intermediate in pIpC-treated mice
|
|
• intermediate in pIpC-treated mice
|
|
• in the bone marrow and spleen of pIpC-treated mice
|
|
• slight reticulin fibrosis in pIpC-treated mice
|
|
• in pIpC-treated mice with increased number of megakaryocytes and clusters of immature erythroid precursors
|
|
• fibrosis in pIpC-treated mice
|
|
• fibrosis in the splenic red and white pulp of pIpC-treated mice
|
|
• intermediate in pIpC-treated mice
|
|
• intermediate in pIpC-treated mice
|
|
• increased Gr-1/Mac-1+ cells in the spleen of pIpC-treated mice
|
|
• in the bone marrow and spleen of pIpC-treated mice
|
|
• intermediate in pIpC-treated mice
|
|
• intermediate in pIpC-treated mice
|
|
• slight reticulin fibrosis in pIpC-treated mice
|
|
• in pIpC-treated mice with increased number of megakaryocytes and clusters of immature erythroid precursors
|
|
• fibrosis in pIpC-treated mice
|
|
• fibrosis in the splenic red and white pulp of pIpC-treated mice
|
|
• mild fibrosis in older pIpC-treated mice
|
|
• fibrosis in the bone marrow cavity of pIpC-treated mice
|
|
• intermediate in pIpC-treated mice
|
|
• intermediate in pIpC-treated mice
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| polycythemia vera | DOID:8997 |
OMIM:263300 |
J:183821 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• unlike Tet2Gt(AN0709)Wtsi homozygous, pIpC-treated mice do not develop a lethal disorder
|
|
• pIpC-treated mice exhibit increased common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP) compared with control mice
• however, pIpC-treated mice exhibit normal numbers of granulocyte-macrophage progenitor cells
|
|
• in the bone marrow of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased CD71+Ter119- proerythroblasts and a decreases CD71lowTer119+ late erythroblasts in the bone marrow compared with control mice
|
|
• pIpC-treated mice exhibit increased numbers of CD71+Ter119+ erythroid cells in the spleen compared with control mice
|
|
• at 4 months in pIpC-treated mice
|
|
• at 4 months in pIpC-treated mice
|
|
• in the bone marrow of pIpC-treated mice
|
|
• modest at 4 months in pIpC-treated mice
|
|
• in the thymus of pIpC-treated mice
|
|
• in the thymus of pIpC-treated mice
|
|
• in the spleen of pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased myelomonocytic CD11b+Gr1- cells in the peripheral blood and spleen compared with control mice
|
|
• pIpC-treated mice exhibit a slight increase in the absolute number of CD150+CD48- LSK cells compared with control mice
|
|
• at 4 months, spleens in pIpC-treated mice exhibit infiltration of the lymphoid follicles with admixed maturing myeloid, immature erythroid, and maturing megakaryocytic elements unlike control mice
|
|
• at 4 months in some pIpC-treated mice
|
|
• at 4 months in pIpC-treated mice
|
|
• at 4 months, pIpC-treated mice exhibit liver sinusoids with a lymphoid and trilineage myeloid elements and some focused perivascular infiltrations unlike control mice
|
|
• at 4 months in some pIpC-treated mice
|
|
• at 4 months, pIpC-treated mice exhibit liver sinusoids with a lymphoid and trilineage myeloid elements and some focused perivascular infiltrations unlike control mice
|
|
• in the bone marrow of pIpC-treated mice
|
|
• in the bone marrow of pIpC-treated mice
|
|
• modest at 4 months in pIpC-treated mice
|
|
• in the thymus of pIpC-treated mice
|
|
• in the thymus of pIpC-treated mice
|
|
• in the spleen of pIpC-treated mice
|
|
• pIpC-treated mice exhibit increased myelomonocytic CD11b+Gr1- cells in the peripheral blood and spleen compared with control mice
|
|
• at 4 months, spleens in pIpC-treated mice exhibit infiltration of the lymphoid follicles with admixed maturing myeloid, immature erythroid, and maturing megakaryocytic elements unlike control mice
|
|
• at 4 months in some pIpC-treated mice
|
|
• at 4 months in pIpC-treated mice
|
|
• in the thymus of pIpC-treated mice
|
|
• at 4 months in some pIpC-treated mice
|
|
• at 4 months in some pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 3 of 6 mice treated with pIpC at 6 - 8 weeks of age died suddenly between 7 - 8 months of age
|
|
• cerebral cavernous malformation like vessels in pIpC treated mice were grossly dilated and exhibited an impaired and disrupted endothelial lumen structure
• cerebral cavernous malformation like lesions were detectable at 3 weeks after pIpC treatment
|
|
• all mice treated with pIpC at 6 - 8 weeks displayed prominent brain hemorrhages at over 7 months of age
• hemorrhages are widespread throughout the brain
• accumulation of hemosiderin in the brain neuronal damage were seen in association with lesions
|
|
• larger hemorrhages were visible most often in the cerebrum and cerebellum
|
|
• larger hemorrhages were visible most often in the cerebrum and cerebellum
|
|
• astrocyte abnormalities indicate an impaired blood-brain barrier in the region of cerebral cavernous malformation like lesions in pIpC treated mice
|
|
• seizure like behavior was seen in 1 mouse, treated with pIpC at 6 - 8 weeks of age, at over 7 months of age
|
|
• cerebral cavernous malformation like vessels in pIpC treated mice were grossly dilated and exhibited an impaired and disrupted endothelial lumen structure
• cerebral cavernous malformation like lesions were detectable at 3 weeks after pIpC treatment
|
|
• all mice treated with pIpC at 6 - 8 weeks displayed prominent brain hemorrhages at over 7 months of age
• hemorrhages are widespread throughout the brain
• accumulation of hemosiderin in the brain neuronal damage were seen in association with lesions
|
|
• larger hemorrhages were visible most often in the cerebrum and cerebellum
|
|
• larger hemorrhages were visible most often in the cerebrum and cerebellum
|
|
• astrocyte abnormalities indicate an impaired blood-brain barrier in the region of cerebral cavernous malformation like lesions in pIpC treated mice
|
|
• microglia were recruited to cerebral cavernous malformation like lesions
|
|
• in pIpC treated mice astrocytes in the region of cerebral cavernous malformation like lesions astrocytes failed to extend their projections to surround capillaries and instead formed abnormal cell clusters
|
|
• seizure like behavior was seen in 1 mouse, treated with pIpC at 6 - 8 weeks of age, at over 7 months of age
|
|
• microglia were recruited to cerebral cavernous malformation like lesions
|
|
• microglia were recruited to cerebral cavernous malformation like lesions
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| cerebral cavernous malformation 2 | DOID:0060670 |
OMIM:603284 |
J:174085 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pIpC-treated mice infected with a retrovirus expression a truncated form of Notch1 that is constitutively cleaved in a ligand-independent manner or a Notch1 lacking the PEST domain exhibit shorted latency to development of leukemia
|
| N |
• pIpC-treated mice exhibit normal numbers of hematopoietic stem cells and are more functionally competent than in cells from Fbxw7tm1Iaai/Fbxw7+ Tg(Mx1-cre)1Cgn mice
|
| N |
• pIpC-treated mice exhibit normal numbers of early T cell progenitors in the thymus
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pIpC-treated mice infected with a retrovirus expression a truncated form of Notch1 that is constitutively cleaved in a ligand-independent manner exhibit shorted latency to development of leukemia
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• no hematopoietic abnormalities observed
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice treated with pI:pC and ENU die rapidly between 2 and 10 months coincident with tumor presentation
|
|
• 47% of 5-10 week old mice treated with pI:pC then treated with ENU develop hematopoietic neoplasms 2-10 months after treatment
|
|
• some pI:pC and ENU treated mice develop thymic derived T cell lymphoblastic lymphomas (17%)
|
|
• some pI:pC and ENU treated mice develop granulocytic sarcoma/acute myeloid leukemia (30%)
|
|
• some pI:pC and ENU treated mice develop granulocytic sarcoma/acute myeloid leukemia (30%); these are solid masses of proliferating myeloblasts which form in retroperitoneum, soft tissue, or in bones of sternum, cranium, or extremities adjacent to soft tissue
• tumor cells disseminate widely, with clusters of cells found in spleen, liver, kidney and lymph nodes
• in some mice, increased myeloblasts are observed in bone marrow, as well as markedly increased white blood cell counts with identifiable circulating leukemic blasts
• tumors are transplantable
|
|
• some pI:pC and ENU treated mice develop thymic derived T cell lymphoblastic lymphomas (17%)
|
| N |
• mimimal abnormalities in hematopoiesis are observed in mutants expressing the Runx1 knock-in allele after pI:pC treatment, although a slight increase in granulocyte-monocyte, mixed and total colonies, as well as in day 12 CFUs in bone marrow, is seen
• no leukemia develops during the first 11months of life of treated mutants
|
|
• 2 mice develop hematopoietic neoplasms by 1 year of age (1 T cell lymphoma, 1 undifferentiated lymphoma)
|
|
• bone marrow cells isolated from mice treated with pI:pC show enhanced replating efficiency in culture; cells are able to form myeloid colonies long after wild-type cells have stopped growing
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die 15 - 21 days after poly IC treatment
|
|
• the number of cells in the hematopoietic stem cell fraction is dramatically reduced in poly IC treated mice
|
|
• bone marrow cells from poly IC treated mice have a reduced capacity to form B-cell progenitors
• cultured B cells trated with IFNG and IL7 to stimulate cre-mediated recombination show about a 70% decrease in the percentage of dividing cells and a 3-fold increase in cells containing 4N DNA
|
|
• decrease in the number and percentage of pre-B to mature-B cells in the bone marrow by 14 days after poly IC treatment
|
|
• decrease in the number and percentage of pro-B cells in the bone marrow by 14 days after poly IC treatment
|
|
• decrease in the number and percentage of the bone marrow myeloid subset by 14 days after poly IC treatment
• bone marrow cells from poly IC treated mice form only a few colonies in all types of myeloid colonies
|
|
• significant reduction in the total number of bone marrow cells by 14 days after poly IC treatment
|
|
• increase in the percentage of Ter119+CD71lo erythroid cells in the bone marrow by 14 days after poly IC treatment
|
|
• bone marrow cells from poly IC treated mice have a reduced capacity to form B-cell progenitors
• cultured B cells trated with IFNG and IL7 to stimulate cre-mediated recombination show about a 70% decrease in the percentage of dividing cells and a 3-fold increase in cells containing 4N DNA
|
|
• decrease in the number and percentage of pre-B to mature-B cells in the bone marrow by 14 days after poly IC treatment
|
|
• decrease in the number and percentage of pro-B cells in the bone marrow by 14 days after poly IC treatment
|
|
• decrease in the number and percentage of the bone marrow myeloid subset by 14 days after poly IC treatment
• bone marrow cells from poly IC treated mice form only a few colonies in all types of myeloid colonies
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• T cell proliferation in response to anti-CD3 antibodies is normal
|
|
• when stimulated by anti-IgM or anti-IgM and IL-4, B cell proliferation is reduced 10-fold
• however, proliferation in response to anti-CD40 antibodies is normal
|
|
• the number of IgM high IgD low immature B cells in the bone marrow is increased compared to in heterzygotes
|
|
• the number of B220+CD43+IgM- pro-B cells in the bone marrow is increased compared to in heterozygotes
|
|
• the number of B220+IgM+ mature B cells in the spleen, bone marrow, and lymph nodes is reduced 2- to 3-fold compared to in heterozygous mice
• the number of IgM low IgD high mature B cells in the bone marrow is reduced compared to in heterozygotes
|
|
• the number of B220+CD43-IgM- pre-B cells in the bone marrow is decreased compared to in heterozygotes
|
|
• anti-TNP IgM responses to a T cell-dependent and -independent antigen are reduced
• however, anti-TNP IgG responses are normal
|
|
• when stimulated by anti-IgM or anti-IgM and IL-4, B cell proliferation is reduced 10-fold
• however, proliferation in response to anti-CD40 antibodies is normal
|
|
• the number of IgM high IgD low immature B cells in the bone marrow is increased compared to in heterzygotes
|
|
• the number of B220+CD43+IgM- pro-B cells in the bone marrow is increased compared to in heterozygotes
|
|
• the number of B220+IgM+ mature B cells in the spleen, bone marrow, and lymph nodes is reduced 2- to 3-fold compared to in heterozygous mice
• the number of IgM low IgD high mature B cells in the bone marrow is reduced compared to in heterozygotes
|
|
• the number of B220+CD43-IgM- pre-B cells in the bone marrow is decreased compared to in heterozygotes
|
|
• when stimulated by anti-IgM or anti-IgM and IL-4, B cell proliferation is reduced 10-fold
• however, proliferation in response to anti-CD40 antibodies is normal
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Increase in cancellous bone mass in Ctsktm1.1Rbar/Ctsktm1.1Rbar Tg(Mx1-cre)1Cgn/0 and Ctsktm1.1Rbar/Ctsktm1.1Rbar Tg(Itgam-cre)AJva/0 mice
|
• CFU-ALP and CFU osteoblasts are increased in pIpC-treated mice compared with controls
• however, the number of CFU fibroblasts is normal
|
|
• in pIpC-treated bone marrow macrophages
|
|
• osteoblasts from the long bones of pIpC-treated mice exhibit increased ALP activity and formed more mineralized bone nodules compared with control cells
• however, osteoblast proliferation is normal
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit reduced resorption pit depths compared with control mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice with reduced trabecular separation
|
|
• in pIpC-treated mice
|
|
• CFU-ALP and CFU osteoblasts are increased in pIpC-treated mice compared with controls
• however, the number of CFU fibroblasts is normal
|
|
• in pIpC-treated bone marrow macrophages
|
|
• osteoblasts from the long bones of pIpC-treated mice exhibit increased ALP activity and formed more mineralized bone nodules compared with control cells
• however, osteoblast proliferation is normal
|
|
• in pIpC-treated bone marrow macrophages
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit reduced resorption pit depths compared with control mice
|
|
• in pIpC-treated bone marrow macrophages
|
|
• in pIpC-treated mice
|
|
• pIpC-treated mice exhibit reduced resorption pit depths compared with control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• disorganization of hepatic lobules and cell swelling
• occasionally observe vacuolated hepatic cells, indicating increased hepatic cell death
|
|
• liver fills up most of the abdominal cavity
|
|
• Cre- induction leads to increases in liver weight with total liver protein weight being twice that of controls
(J:130839)
|
|
• hepatocytes lack typical glycogen area, contain aberrant concentric membranous structures that originate form the rough ER and surround various cytoplasmic constituents, and accumulate peroxisomes and deformed mitochondria
(J:100199)
• accumulation of ubiquitin-positive inclusions in the cytoplasm
(J:100199)
• cytoplasmic inclusion bodies that contain ubiquitinated proteins occur in the hepatocytes of mice expressing Cre
(J:130839)
|
|
• autophagosome formation in the liver under fasting conditions is not induced in homozygotes
• fasting-induced degradation of cytosolic proteins and mitochondria in the liver does not occur as in controls
|
|
• hepatocyte proliferation increases after Cre-induction
|
|
• liver function is decreased after Cre-induction with increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) apparent in the serum
|
|
• the hepatocytes of mice expressing Cre have defects in autophagy leading to a build up of cytoplamsic inclusion bodies that contain ubiquitinated proteins
|
|
• lower concentration of amino acids in fasted hepatocytes
|
|
• leakage of alanine transaminase
(J:100199)
• very high levels of AST are found in the sera after Cre-induction due to liver failure
(J:130839)
|
|
• leakage of alkaline phosphatase
(J:100199)
• high levels of ALP are found in the sera after Cre-induction due to liver failure
(J:130839)
|
|
• leakage of aspartate transaminase
(J:100199)
• very high levels of AST are found in the sera after Cre-induction due to liver failure
(J:130839)
|
|
• the hepatocytes of mice expressing Cre have defects in autophagy leading to a build up of cytoplamsic inclusion bodies that contain ubiquitinated proteins
|
|
• hepatocyte proliferation increases after Cre-induction
|
|
• liver fills up most of the abdominal cavity
|
|
• Cre- induction leads to increases in liver weight with total liver protein weight being twice that of controls
(J:130839)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• granulocytes maintained c-kit expression and displayed some, but not complete, maturation
|
|
• spleen cells generated vastly increased numbers of granulocytic colonies, excessive numbers of megakaryocytic colonies and IL-3 responsive macrophage-containing colonies
|
|
• the bone marrow contained normal total cellularity but exhibited an increased proportion of blast cells, and immature cells of the granulocyte lineage (promyelocytes and myelocytes)
|
|
• bone marrow lacked eosinophil colony-forming cells that were responsive to granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3 or IL-5, but had greatly elevated numbers of granulocytic colonies developed when stimulated by G-CSF, IL-3 or stem cell factor but not with IL-6
• few or no megakaryoctye colonies developed in cultures of bone marrow cells under optimal culture for megakaryoctye formation
• loss of any readily identifiable lymphoid and myeloid progenitor or stem cell populations
|
|
• bone marrow lacked the nucleated erythroid cells that represent 17% of the control bone marrow
|
|
• expansion of granulocyte precursors in the bone marrow and spleen
|
|
• B lymphocyte numbers were reduced variably in the bone marrow, with most cells having a preB cell phenotype
|
|
• in severe cases, spleen showed homogeneous infiltration by immature granulocytic forms and loss of splenic architecture
|
|
• granulocytes maintained c-kit expression and displayed some, but not complete, maturation
|
|
• expansion of granulocyte precursors in the bone marrow and spleen
|
|
• B lymphocyte numbers were reduced variably in the bone marrow, with most cells having a preB cell phenotype
|
|
• in severe cases, spleen showed homogeneous infiltration by immature granulocytic forms and loss of splenic architecture
|
|
• granulocytes maintained c-kit expression and displayed some, but not complete, maturation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• the proportion and total number of B cells were increased in spleen and lymph nodes
|
|
• the increased number of marginal zone B cells results in an expansion of the marginal zone
|
|
• the proportion and total number of marginal zone B cells was increased by 3-fold and 5- fold, respectively
|
|
• the proportion and total number of B cells were increased in spleen and lymph nodes
|
|
• the increased number of marginal zone B cells results in an expansion of the marginal zone
|
|
• the proportion and total number of marginal zone B cells was increased by 3-fold and 5- fold, respectively
|
|
• the proportion of B cells was doubled, the total B cell numbers were increased 4-fold and B cells were increased in size in the lymph nodes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• liver was normal at 3 weeks after transgene induction
• 6 months after transgene induction, liver contained an accumulation of small lipid droplets (microvesicular steatosis) but no fibrosis
|
|
• regeneration of the liver after partial hepatectomy is impaired
• growth factors in the blood such as HGF/SF and Il6 peak a little later than in wild-type mice (6-12 hours as opposed to 6 hours postoperatively)
• growth factor levels remain elevated longer (still high at 46 hours postoperative)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• adult mice developed a wasting syndrome and died 2 to 4 weeks after induction of cre recombinase
|
|
• the endothelial cells lining the blood vessels became round, irregularly aligned, and apoptotic
|
|
• multifocal cellular plaques containing large round cells observed in the ventricle
|
|
• diffused degeneration of myocardial fibers was observed along with multifocal inflammatory changes
|
|
• multifocal acute hemorrhages in multiple organs including the heart, brain, and lung
• associated with abnormal endothelial cells
|
|
• blood vessels became abnormally leaky
|
|
• apoptosis of endothelial cells leading to increased vascular permeability and hemorrage
|
|
• diffused degeneration of myocardial fibers was observed along with multifocal inflammatory changes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mutants injected with pIpC to induce expression of Cre recombinase exhibit normal myeloid cell development, neutrophil counts, hemoglobin levels, and maintenance of hematopoietic stem cells in adults
|
|
• pIpC treated mutants exhibit an increase in apoptosis of myeloid colony-forming cells
|
|
• pIpC treated mutants exhibit a significant block in the maturation of T-cell progenitors at the transition from CD44+CD25+ (double negative 2) to CD44-CD25+ (double negative 3), indicating the accumulation of immature T-cell precursors in the thymus
|
|
• the immature megakaryocytes observed in bone marrow of mutants injected with pIpC exhibit poorly demarcated membranes and a lower level of polyploidy than controls
|
|
• after injection of pIpC to induce expression of Cre recombinase, bone marrow exhibits an arrest in megakaryocytic maturation
|
|
• after injection of pIpC to induce expression of Cre recombinase, mutants exhibit an increase in hematopoietic progenitor cells
• bone marrow cells from pIpC injected mutants form more megakaryocytic (CFU-Meg), myeloid, and mixed (myeloid and erythroid) colonies in vitro than control bone marrow cells
|
|
• immediately after injection of pIpC to induce expression of Cre recombinase, mice show a decline in platelet counts to 1/3 to 1/6 of those for the control
|
|
• pIpC treated mutants exhibit a significant block in the maturation of T-cell progenitors at the transition from CD44+CD25+ (double negative 2) to CD44-CD25+ (double negative 3), indicating the accumulation of immature T-cell precursors in the thymus
|
|
• after injection of pIpC to induce expression of Cre recombinase, bone marrow exhibits an arrest in megakaryocytic maturation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• normal histological appearance of the liver
• normal serum transaminase levels
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• reduced number of marginal zone B cells in the spleen
|
| N |
• mutants exhibit normal T cell development
|
|
• reduced number of marginal zone B cells in the spleen
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 5% lethality, surviving mutants had an intact floxed allele
|
|
• moderate anemia at 4 and 2 weeks after the initiation of poly(I)-poly(C) (pIpC) treatment to induce cre expression
|
|
• moderate thrombocytopenia at 2 and 4 weeks after the initiation of pIpC treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• T cell acute lymphoblastic leukemia (T-ALL)
• progressive leukemic cells infiltrate the leptomeningeal spaces of the brain
|
|
• atypical CD4+CD8+ T cells in the peripheral blood
|
|
• atypical CD4+CD8+ T cells in the peripheral blood
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increased TNF and IL-6 production by peritoneal macrophages stimulated by LPS and IFN-gamma, relative to those of wild-type
|
|
• increased IL-6 production by peritoneal macrophages stimulated by LPS and IFN-gamma, relative to those of wild-type
|
|
• increased TNF production by peritoneal macrophages stimulated by LPS and IFN-gamma, relative to those of wild-type
|
|
• increased TNF and IL-6 production by peritoneal macrophages stimulated by LPS and IFN-gamma, relative to those of wild-type
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• platelet thrombus formation is severely impaired ex vivo after treatment of platelets with polyinosinic-polycytidylic acid (PIPC) to induce recombination
• however, initial adhesion of platelets ex vivo is similar to wild-type
• in wild-type mice transfected with Gna13-deficient bone marrow, after vascular injury no thrombi form
|
|
• impairment in shape change and aggregation induced following polyinosinic-polycytidylic acid (PIPC) treatment is identical to that in mice that are also homozygous for Gna12tm1Citb
• serotonin secretion induced by U46619 plus adrenaline or Par-4 peptide exposure is significantly decreased compared to wild-type cells
• however, thrombin-induced serotonin secretion is not impaired
• in wild-type mice transfected with Gna13-deficient bone marrow, platelets adhere to subendothelial surface after injury, but with a ~50% reduction in numbers compared to wild-type platelets
|
|
• very large increase in bleeding time in interferon-responsive tissues
• when bone marrow-derived cells PIPC-treated mice are transplanted into irradiated wild-type mice, 4 weeks later mice have greatly prolonged bleeding times (>20 minutes) compared with mice receiving cells from noninduced controls
|
|
• impairment in shape change and aggregation induced following polyinosinic-polycytidylic acid (PIPC) treatment is identical to that in mice that are also homozygous for Gna12tm1Citb
• serotonin secretion induced by U46619 plus adrenaline or Par-4 peptide exposure is significantly decreased compared to wild-type cells
• however, thrombin-induced serotonin secretion is not impaired
• in wild-type mice transfected with Gna13-deficient bone marrow, platelets adhere to subendothelial surface after injury, but with a ~50% reduction in numbers compared to wild-type platelets
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• peripheral and bone marrow hematopoietic cell counts are similar to controls at 8 weeks after pIpC treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• hematopoietic stem cells numbers and long-term multi-lineage reconstitution function are normal in pIpC-treated mice
|
|
• 2-fold in pIpC treated mice
|
| N |
• hematopoietic stem cells from pIpC treated mice exhibit normal reactive oxygen species or aneuploidy in culture
|
|
• in the hematopoietic stem cells of pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in pIpC-treated mice
|
|
• following pIpC treatment, multipotent progenitors transiently expand then are depleted in parallel with hematopoietic stem cells unlike in Stk11tm1Sjm homozygotes
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• 18 days after pIpC treatment; not improved by rapamycin treatment
|
|
• by day 24 to 34 of pIpC treatment
|
|
• starting 2 to 6 days after pIpC treatment
|
|
• hematopoietic stem cells (HSCs)from pIpC-treated mice exhibit increased cell proliferation compared with cells from Stk11tm1Sjm homozygotes
• 11 days after pIpC-treatment, HSCs exhibit increased apoptosis compared with cells from Stk11tm1Sjm homozygotes
• HSCs from pIpC-treated mice fail to exhibit long-term reconstitution unlike cells from Stk11tm1Sjm homozygotes
• however, mice exhibit normal proliferation of granulocyte macrophage progenitors (GMP) and whole bone marrow (WBM) cells and apoptosis of multipotent progenitor, GMP, and WBM cells
|
| N |
• hematopoietic stem cells from pIpC treated mice exhibit normal reactive oxygen species
|
|
• hematopoietic stem cells from pIpC-treated mice become aneuploid unlike similarly treated cells from Stk11tm1Sjm homozygotes
• however, granulocyte macrophage progenitors cells from pIpC-treated mice do not become aneuploid
|
|
• hematopoietic stem cells from pIpC-treated mice exhibit supernumerary centrosomes and defective mitotic spindle unlike in cells from similarly treated Stk11tm1Sjm homozygotes
|
|
• in the hematopoietic stem cells of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice develop microcytic and hypochromic anemia following polyinosinicpolycytidylic acid (pIpC) treatment
|
|
• decreased number of mature (R4) erythroblasts in the spleen in proportion to number of R2 erythroblasts
|
|
• increased numbers of immature (R2) erythroblasts in the spleen in proportion to number of R4 erythroblasts
|
|
• variation in red blood cell size and shape
|
|
• impaired transition of stage III (poly-chromatophilic) to stage IV (ortho-chromatophilic) erythroblasts
• increase in erythroblast apoptosis
• decrease in number of fully-formed clathrin coated pits in erythroblast
|
|
• reduced numbers of red blood cells in peripheral blood following pIpC treatment
|
|
• reduced hematocrit levels in peripheral blood following pIpC treatment
|
|
• reduced hemoglobin levels in peripheral blood following pIpC treatment
• reticulocytes have a low hemoglobin content
|
|
• decreased mean corpuscular volume following pIpC treatment
|
|
• decreased mean corpuscular hemoglobin following pIpC treatment
|
|
• increased red cell distribution width in peripheral blood following pIpC treatment
|
|
• decreased numbers of CD4+ T cells beginning 3 months after pIpC treatment
|
|
• decreased numbers of CD8+ T cells beginning 5 months after pIpC treatment
|
|
• elevated reticulocyte counts
• increase in percentage of immature reticulocyte fraction
|
|
• high serum erythropoietin levels beginning 2 months after pIpC treatment
|
|
• increased amounts of surface-bound transferrin in relation to internalized transferrin on erythroblasts as compaired to wild-type
• transferrin receptor endocytosis is 25% as efficient as wild-type
|
|
• elevated serum iron levels
|
|
• decreased numbers of CD4+ T cells beginning 3 months after pIpC treatment
|
|
• decreased numbers of CD8+ T cells beginning 5 months after pIpC treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• pIpC-treated mice die within two weeks of treatment
|
|
• bone marrow cells from pIpC-treated mice fail to form colonies in culture
|
|
• in pIpC-treated mice
|
|
• in the bone marrow of pIpC-treated mice
|
|
• in the bone marrow cells from pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• increased apoptosis in the bone marrow of pIpC-treated mice
• bone marrow cells from pIpC-treated mice exhibit impaired hematopoietic reconstitution compared with with cells from control mice
|
|
• increased apoptosis in the bone marrow of pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• lethally irradiated mice transplanted with mutant bone marrow cells followed by pIpC injection develop anemia with increased mean corpuscular volume and red blood cell distribution width
|
|
|
• lethally irradiated mice transplanted with mutant bone marrow cells followed by pIpC injection exhibit reduced white blood cell count, with a reduction in lymphocytes, granulocytes, and monocytes
|
|
|
• lethally irradiated mice transplanted with mutant bone marrow cells followed by pIpC injection exhibit increased frequency of immature bone marrow progenitors (LSK cells)
|
|
|
• lethally irradiated mice transplanted with mutant bone marrow cells followed by pIpC injection exhibit lineage-committed mature cells that are skewed to myeloid lineages
|
|
|
• lethally irradiated mice transplanted with mutant bone marrow cells followed by pIpC injection show reduced frequency of colony-forming unit erythroid cells and Ter119+CD71+ erythroid progenitors
|
|
|
• lethally irradiated mice transplanted with mutant bone marrow cells followed by pIpC injection show increased mean corpuscular volume
|
|
|
• lethally irradiated mice transplanted with mutant bone marrow cells followed by pIpC injection show increased red blood cell distribution width
|
|
|
• all lethally irradiated mice transplanted with mutant-derived bone marrow, followed by pIpC injection, develop overt myelodysplastic syndrome, mostly within half a year after pIpC injection, with severe cytopenia and marked trilineage dysplasia
|
|
|
• lethally irradiated mice transplanted with mutant bone marrow cells followed by pIpC injection exhibit reduced white blood cell count, with a reduction in lymphocytes, granulocytes, and monocytes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• pIpC-injected mice exhibit mild myelodysplastic syndrome-like phenotype
• however, overall survival does not differ from wild-type mice
• mice show decreased frequencies of megakaryocyte/erythrocyte lineage-restricted progenitors and erythroid progenitors after pIpC injection, suggesting a blocked differentiation into erythromegakaryocyte lineages
|
|
|
• slightly enlarged spleen in pIpC-treated mice
|
|
|
• pIpC-injected mice show evidence of extramedullary hematopoiesis, with increased frequencies of erythroid progenitors in the spleen
|
|
|
• pIpC-injected mice show increased red cell distribution width, suggestive of dyerythropoiesis
|
|
|
• mature cells are skewed to myeloid lineages in pIpC-injected mice with increased granulocytes/monocytes (CD11b+) in the bone marrow and spleen
|
|
|
• mature cells are skewed to myeloid lineages in pIpC-injected mice with increased granulocytes/monocytes (CD11b+) in the bone marrow and spleen
|
|
|
• mice show a slightly decreased white blood cell count after polyinosinic-polycytidylic acid (pIpC) injection
• however, no changes in hemoglobin level or platelet count after pIpC injection
|
|
|
• mice show a large reduction of B-lymphocytes (B220+) after pIpC injection
|
|
|
• hematopoietic stem/progenitor cell pools are expanded in pIpC-injected mice
|
|
|
• the increase in LSK cells of pIpC-injected mice is most prominent in myeloid-based progenitors, including multipotent progenitor 2 and 3, followed by long-term hematopoietic stem cells and short-term hematopoietic stem cells, indicating myeloid skewing
|
|
|
• common myeloid progenitors and granulocyte-macrophage progenitors are increased in pIpC-treated mice
|
|
|
• common lymphoid progenitors are decreased in pIpC-treated mice
|
|
|
• mice show decreased frequency of erythroid progenitors after pIpC injection
|
|
|
• bone marrow of pIpC-injected mice shows higher frequency of Lin-/Sca1+/c-Kit+ (LSK) cells, where all major subfractions of LSK cells are increased
|
|
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• mice show decreased frequencies of megakaryocyte/erythrocyte lineage-restricted progenitors following pIpC injection
|
|
|
• hematopoietic stem cells (CD150+/CD48- LSK) show a decreased frequency of apoptotic cells and an enhanced cell cycling (S/G2/M) with decreased quiescent cells after pIpC injection
• in competitive repopulation assay, cells from pIpC-injected mice show enhanced chimerism within the LSK fraction, although the chimerism is not changed in total bone marrow and even reduced in peripheral blood, particularly within lymphocytes, indicating an enhanced self-renewal and repopulation capacity of progenitors with a block in lymphoid differentiation
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• slightly enlarged spleen in pIpC-treated mice
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• mature cells are skewed to myeloid lineages in pIpC-injected mice with increased granulocytes/monocytes (CD11b+) in the bone marrow and spleen
|
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• mature cells are skewed to myeloid lineages in pIpC-injected mice with increased granulocytes/monocytes (CD11b+) in the bone marrow and spleen
|
|
|
• mice show a slightly decreased white blood cell count after polyinosinic-polycytidylic acid (pIpC) injection
• however, no changes in hemoglobin level or platelet count after pIpC injection
|
|
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• mice show a large reduction of B-lymphocytes (B220+) after pIpC injection
|
|
|
• slightly enlarged spleen in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice injected with pIpC show increased plasma homogentisic acid (HGA) levels
|
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• mice show a relatively small increase in urinary HGA following pIpC injection
|
|
• mice show a relatively small increase in urinary HGA following pIpC injection
|
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• few or no pigmented chondrons are seen in the calcified articular cartilage of knee joints at 9 weeks post pIpC injection, but increased numbers are seen at 15 and 20 weeks post pIpC
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• bone marrow cells from pIpC-treated mice fail to form fewer colonies in culture compared with control cell
|
|
• modest reduction in pIpC-treated mice
|
|
• in the bone marrow cells from pIpC-treated mice with an increase in the percentage of LK cells, decrease in LSK cells and increased proportion of short-term SLAM+ cells
|
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• modest increase in apoptosis in the bone marrow of pIpC-treated mice
|
|
• modest increase in apoptosis in the bone marrow of pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• bone marrow cell mitochondria of pI-pC treated mice show prominent contours of the membranes and are swollen
• accumulation of iron in mitochondria of bone marrow cells of pI-pC treated mice
|
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• pI-pC treated mice show impaired erythroid cell maturation
|
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• pI-pC treated mice develop anemia; anemia is classified as microcytic and hypochromic type
|
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• pI-pC treated mice exhibit a decrease in red blood cell number
|
|
• heme is reduced in the peripheral blood of pI-pC treated mice
|
|
• pI-pC treated mice show a decrease in hemoglobin
• however, white blood cell number and platelet count are normal
|
|
• low mean corpuscular hemoglobin concentration in pI-pC treated mice
|
|
• low mean corpuscular volume in pI-pC treated mice
|
|
• pI-pC treated mice show an increase in the number of reticulocytes
|
|
• pI-pC treated mice exhibit accumulation of iron in mitochondria
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• pIpC-treated mice show normal erythroid and myeloid development and no changes in the hematopoietic stem cell (HSC) population relative to controls
• no differences in the common myeloid progenitor population (CMP) or the downstream granulocyte/monocyte progenitor (GMP) and megakaryocyte/erythroid progenitor (MEP) populations are observed
• B cells produce normal serum IgG levels and are able to proliferate normally and differentiate into plasma cells during ex vivo culture upon LPS stimulation
|
|
• pIpC-treated mice show reduced formation of early B cell progenitors in the bone marrow
• ex vivo, Lin- cells co-cultured with OP9 stromal cells in the presence of IL7 and Flt3L (to promote B cell development) do not exhibit any B220+ B cell growth, suggesting that stem cells fail to differentiate into committed progenitor B cells
|
|
• pIpC-treated mice show decreased immature B cell populations in the bone marrow
• however, mature recirculating B cell numbers are normal
|
|
• pIpC-treated mice show a significant decrease in the transitional T1-T2 cell population in the spleen
|
|
• pIpC-treated mice show decreased pro-B cell populations in the bone marrow
|
|
• pIpC-treated mice show decreased pre-pro B cell populations in the bone marrow
|
|
• pIpC-treated mice show ~2 fold reduction in the common lymphocyte progenitor (CLP) population in the bone marrow
• most of this reduction is due to reduced B cell biased lymphoid progenitor (BLP) numbers
• all lymphoid progenitor (ALP) numbers are only modesty reduced
|
|
• pIpC-treated mice show a modest increase of B-1a cells in the peritoneal cavity
• however, B2 cell numbers are normal
|
|
• pIpC-treated mice show a significant increase in the follicular zone population in spleen
|
|
• pIpC-treated mice show a 2-fold decrease in B (B220+) cells in the bone marrow
• analysis of B cell populations using Hardy fraction cell surface markers (B220, CD43, BP-1, HSA, IgM, and IgD) showed significant decreases in all B cell populations, except for the C population
• mature/recirculating B cells (fraction F) are only modestly reduced
|
|
• pIpC-treated mice show a modest decrease of B-1b cells in the peritoneal cavity
|
|
• pIpC-treated mice show decreased pre-pro B cell populations in the bone marrow
|
|
• pIpC-treated mice show a modest but significant decrease of CD4+ T cells in the thymus
• thymic double positive (CD4+ CD8+) cells and single CD8+ T cell populations are normal
• no significant differences are observed in splenic CD4+ and CD8+ T cell populations
|
|
• pIpC-treated mice show reduced formation of early B cell progenitors in the bone marrow
• ex vivo, Lin- cells co-cultured with OP9 stromal cells in the presence of IL7 and Flt3L (to promote B cell development) do not exhibit any B220+ B cell growth, suggesting that stem cells fail to differentiate into committed progenitor B cells
|
|
• pIpC-treated mice show decreased immature B cell populations in the bone marrow
• however, mature recirculating B cell numbers are normal
|
|
• pIpC-treated mice show a significant decrease in the transitional T1-T2 cell population in the spleen
|
|
• pIpC-treated mice show decreased pro-B cell populations in the bone marrow
|
|
• pIpC-treated mice show decreased pre-pro B cell populations in the bone marrow
|
|
• pIpC-treated mice show a modest increase of B-1a cells in the peritoneal cavity
• however, B2 cell numbers are normal
|
|
• pIpC-treated mice show a significant increase in the follicular zone population in spleen
|
|
• pIpC-treated mice show a 2-fold decrease in B (B220+) cells in the bone marrow
• analysis of B cell populations using Hardy fraction cell surface markers (B220, CD43, BP-1, HSA, IgM, and IgD) showed significant decreases in all B cell populations, except for the C population
• mature/recirculating B cells (fraction F) are only modestly reduced
|
|
• pIpC-treated mice show a modest decrease of B-1b cells in the peritoneal cavity
|
|
• pIpC-treated mice show decreased pre-pro B cell populations in the bone marrow
|
|
• pIpC-treated mice show a modest but significant decrease of CD4+ T cells in the thymus
• thymic double positive (CD4+ CD8+) cells and single CD8+ T cell populations are normal
• no significant differences are observed in splenic CD4+ and CD8+ T cell populations
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• white blood cell count at age 18 months
|
|
• at age 18 months
|
|
• progressive anemia, with severe drop in reticulocyte count from 550 days of age, resulting in death of some mice
• impaired erythropoiesis at transition from CD71+ Ter119+ basophilic and early chromatophilic erythroblasts (RII stage) to intermediate-CD71 Ter119+ polychromatophilic (RIII) to low-CD71 Ter119+ orthochromatophilic erythroblasts and enucleated erythrocytes (RIV) at age 18 months
• impaired differentiation at RIIIRIV stage transition with a decrease in quiescence of cells in RI stage population at 22 weeks of age
• development of more severe anemia and delayed reticulocyte response after induction of acute hemolytic stress with phenylhydrazine
• RI stage population (CD71+ Ter119-) significantly increased and RIV stage population (low-CD71 high-Ter119) significantly decreased after induction of acute hemolytic stress with phenylhydrazine
• terminal erythroid differentiation defect
• failure of hematopoietic stem and progenitor cells (HSPCs) to differentiate after 5 days culture in vitro
|
|
• substantially increased numbers of hypolobulated micro-megakaryocytes at age 18 months
|
|
• significant reduction in protein synthesis according to O-propargyl-puromycin (OP-puro) incorporation assay
|
|
• mild, in peripheral blood smears at age 18 months
|
|
• dysplasia in peripheral blood smears at age 18 months
|
|
• diffuse hemosiderin deposits at age 18 months
|
|
• significantly shorter telomeres in bone marrow cells
|
|
• significantly smaller percentage of bone marrow long-term hematopoietic stem cells (LT-HSCs) in G0 phase
• significantly higher percentage of LT-HSCs in G1 and S-G2-M phases
|
|
• in RIII (intermediate-CD71 Ter119+) erythroblasts
|
|
• significant reduction in protein synthesis in bone marrow according to O-propargyl-puromycin (OP-puro) incorporation assay
|
|
• significantly increased frequency of long-term hematopoietic stem cells (LT-HSCs; lineage-low c-Kit+ Sca1+ CD48- CD150+) and multipotent progenitor cells (MPPs; lineage-low c-Kit+ Sca1+ CD48+ CD150-) in bone marrow at age 18 months
• diffuse hemosiderin deposits at age 18 months
• slightly decreased cellularity at age 18 months
• substantially increased numbers of hypolobulated micro-megakaryocytes at age 18 months
|
|
• at age 18 months
|
|
• significant reduction in protein synthesis in bone marrow according to O-propargyl-puromycin (OP-puro) incorporation assay
|
|
• at age 18 months
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 10 to 14 days after pIpC treatment
|
|
• aplasia in pIpC-treated mice
|
|
• reduced frequencies and total number in the bone marrow of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• reduced frequencies and total number in the bone marrow of pIpC-treated mice
|
|
• reduced frequencies and total number in the bone marrow of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• decreased frequency and absolute numbers of LSK and long-term hematopoietic stem cells, short-term hematopoietic stem cells, and multipotent progenitors in the bone marrow of pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• impaired repopulation capacity of hematopoietic stem cells with increased cell death and DNA damage in pIpC-treated mice
|
|
• cell autonomous, primary and in bone marrow transplantation experiments, in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• in pIpC-treated mice
|
|
• cell autonomous, primary and in bone marrow transplantation experiments, in pIpC-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice exhibit normal and malignant hematopoiesis
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• polyI:C-treated mice exhibit splenomegaly
|
|
• polyI:C-treated mice exhibit ineffective erythropoiesis in which most of the erythroid precursors are blocked in the orthochromatic to reticulocyte stages
• bone marrow erythroblasts from populations I to III (proerythroblasts, basophilic erythroblasts, and polychromatic erythroblasts) are proportionally increased while populations IV to VI (orthochromatic erythroblasts, reticulocytes, and mature red blood cells), especially the reticulocytes are decreased
• populations I to III (proerythroblasts, basophilic erythroblasts, and polychromatic erythroblasts) are proportionally increased in the spleen
• Ter119+ erythroblasts from both bone marrow and spleen show an increase in G2/M phase and most of the binucleated erythroblasts are in stage IV orthochromatic phase of differentiation in bone marrow
• a small portion of the erythroid cells in bone marrow, but not spleen, undergo cell death
|
|
• polyI:C-treated mice exhibit an extramedullary erythropoiesis in the spleen that compensates ineffective erythropoiesis in bone marrow
|
|
• mice induced with polyinosinic-polycytidylic acid (polyI:C) at 6 weeks of age exhibit anemia at 10 weeks after induction
|
|
• mice exhibit decreased total red blood count following induction with polyI:C
|
|
• mice exhibit decreased hematocrit following induction with polyI:C
|
|
• mice exhibit decreased hemoglobin following induction with polyI:C
|
|
• red cell distribution width is increased, indicating variation in size of red blood cells, in polyI:C treated mice
|
|
• polyI:C-treated mice exhibit anemia with anisopoikilocytosis including macrocytes, microcytes, occasional spherocytes, and hypochromic cells
|
|
• polychromasia is increased with abnormally large reticulocytes
|
|
• polyI:C-treated mice exhibit splenomegaly
|
|
• polyI:C-treated mice exhibit splenomegaly
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| congenital dyserythropoietic anemia | DOID:1338 |
OMIM:PS224120 |
J:293763 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• strongly increased tumour incidence of T-ALL with elevated ICN1 levels in mutant tumors
|
|
• strongly increased tumour incidence of T-ALL with elevated ICN1 levels in mutant tumors
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• after cre induction using pIpC
• hematological abnormalities in all mice after 16 months
|
|
• splenomegaly
• myeloid infiltration
|
|
• defective erythroid development
|
|
• increased number of mature cells
|
|
• low white blood cell count
• dysplastic peripheral myeloid cells
|
|
• after cre induction by pIpC
• in 11 months
|
|
• after cre induction by pIpC
• 13% succumb to myeloid leukemia by 11 months
• 70% die within two years
|
|
• splenomegaly
• myeloid infiltration
|
|
• increased number of mature cells
|
|
• low white blood cell count
• dysplastic peripheral myeloid cells
|
|
• after cre induction by pIpC
• in 11 months
|
|
• splenomegaly
• myeloid infiltration
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• median survival of 149 days
|
|
• all mice remain in the chronic phase of myeloid leukemia
|
|
• upon withdrawal of tetracycline, mice develop moderate, but persistent (2-3 fold) increase of white blood counts
|
|
• upon withdrawal of tetracycline, mice show marked expansion of the granulocyte compartment
|
|
• upon withdrawal of tetracycline, mice develop moderate, but persistent (2-3 fold) increase of white blood counts
|
|
• upon withdrawal of tetracycline, mice show marked expansion of the granulocyte compartment
|
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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last database update 04/16/2024 MGI 6.23 |
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