Analysis Tools
mortality/aging
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• homozygous mice begin to die after 7 months of age and the median life span of females is reduced to 16 months compared to about 22 months for wild-type
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cellular
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• splenocytes and keratinocytes have 3 or more centrosomes per cell and many keratinocytes have asymmetric distribution of centrosomes during mitosis
• most MEFs with extra centrosomes also have large, partially cleaved, bilobed nuclei
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• most MEFs with extra centrosomes also have large, partially cleaved, bilobed nuclei
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• chromosomal aberrations including double minutes, centromere fusions or end associations, chromatid deletions, and incomplete triradials and quadraradials
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• less than 40% of homozygous MEFs are diploid at passage 4 with the rest either tetraploid or aneuploid, unlike wild-type MEFs where about 70% of cells are diploid, 30% are tetraploid and no aneuploid cells are seen
• at passage 11 no homozygous MEFs are diploid and over 60% are aneuploid
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aneuploidy
(
J:57882
)
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• at passage 4 some aneuploid cells are seen and by passage 11 over 60% of cells are aneuploid
• about 2% of freshly isolated splenic lymphoblasts display aneuploidy while no aneuploid cells are found in wild-type mice
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• diffuse global mesangial proliferation involving 40 - 100% of glomeruli is seen in older homozygotes
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• in some glomeruli
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• retroviral transfection of homozygous MEFs with an activated ras allele produces obvious transformed foci and these cells are able to form colonies in soft agar, unlike wild-type MEFs where the introduction of 2 activated oncogenes is needed for transformation
• the number of colonies produced in the soft agar assay is less than in transfected homozygous Trp53 null MEFs
• however, when exposed to ionizing radiation or UV apoptosis is similar to wild-type unlike Trp53 null MEFs
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• some MEFs fail to fully condense all their chromatin at mitosis
• IR induces a strong G1 delay similar to wild-type cells and unlike in Cdkn1a null cells
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• when exposed to UV the dose dependent reduction in the mitotic index is decreased compared to wild-type cells; however, when exposed to ionizing radiation (IR), the reduction in mitotic index is similar to wild-type and IR or UV-induced apoptosis is similar to wild-type unlike Trp53 null MEFs
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• the sensitivity of primary T cell activation by anti-CD3 is increased with a 3- to 10-fold leftward shift in the dose-response curve and the maximal proliferative response is about 2-fold more than in wild-type cells
• however, proliferation in response to cytokines and T cell receptor independent proliferation is not increased compared to controls
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• from passage 5-7 homozygous MEFs progressively grow more rapidly and attain higher saturation densities compared to wild-type cells; however at earlier passages growth is similar to wild-type
• low passage MEFs have a plating efficiency of about 0.025% compared to 0.005% in wild-type cells, 1.6% in Trp53 null cells, 1.2% in Cdkn1a null cells, and up to 1.4% in Gadd45a Cdkn1a double null cells
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• diffuse global mesangial proliferation involving 40 - 100% of glomeruli is seen in older homozygotes
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hematopoietic system
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• the sensitivity of primary T cell activation by anti-CD3 is increased with a 3- to 10-fold leftward shift in the dose-response curve and the maximal proliferative response is about 2-fold more than in wild-type cells
• however, proliferation in response to cytokines and T cell receptor independent proliferation is not increased compared to controls
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• thymus weight as a percent of body weight is increased about 70% compared to wild-type
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• lymphoid hyperplasia is seen in the lymph nodes and spleen of 9 month old homozygotes
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• increased apoptosis induced by UV, daunorubicin, or VP-16 is seen in bone marrow cells
• after UV chemotherapy or treatment with daunorubicin, or VP-16 homozygous bone marrow cells yield 6-fold or 8-16-fold, respectively, fewer IL-3 stimulated colonies compared to wild-type cells
• following treatment with UV or VP-16, but not daunorubicin, homozygous bone marrow cells fail to arrest at G2/M unlike wild-type cells
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• the proportion of total T cells is increased in the spleen and lymph nodes compared to wild-type mice
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• thymocyte number is increased but the distribution of thymocyte subpopulations is similar to wild-type
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• at 7-9 months of age 47% of homozygous females are leukopenic compared to 7% of wild-type mice
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• at 7-9 months of age 40% of homozygous females are lymphopenic compared to 7% of wild-type mice
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• 2-fold increase in IgG1 and high levels of IgG2b and IgG3 anti-double stranded DNA antibodies at 7 - 9 months of age
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• 2-fold increase in IgM at 7 - 9 months of age
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immune system
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• the sensitivity of primary T cell activation by anti-CD3 is increased with a 3- to 10-fold leftward shift in the dose-response curve and the maximal proliferative response is about 2-fold more than in wild-type cells
• however, proliferation in response to cytokines and T cell receptor independent proliferation is not increased compared to controls
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• thymus weight as a percent of body weight is increased about 70% compared to wild-type
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• lymphoid hyperplasia is seen in the lymph nodes and spleen of 9 month old homozygotes
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• the proportion of total T cells is increased in the spleen and lymph nodes compared to wild-type mice
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• thymocyte number is increased but the distribution of thymocyte subpopulations is similar to wild-type
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• at 7-9 months of age 47% of homozygous females are leukopenic compared to 7% of wild-type mice
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• at 7-9 months of age 40% of homozygous females are lymphopenic compared to 7% of wild-type mice
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• 2-fold increase in IgG1 and high levels of IgG2b and IgG3 anti-double stranded DNA antibodies at 7 - 9 months of age
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• 2-fold increase in IgM at 7 - 9 months of age
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• after 7 months of age in female homozygotes the occurrence and titer of antibodies against double stranded DNA is increased compared to wild-type mice
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• after 7 months of age in female homozygotes the occurrence and titer of antibodies against histones is increased compared to wild-type mice
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• after 7 months of age in female homozygotes the occurrence and titer of antibodies against single stranded DNA is increased compared to wild-type mice
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• lymphocytic infiltrates are seen in the lung and salivary glands at 9 months of age
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• some glomeruli contain inflammatory cells, nuclear debris, and mesangial cell interposition, mild dilation of the proximal tubules occurs, and mild to severe dense perivascular mononuclear cell infiltrates are seen suggesting autoimmune glomerulonphritis
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nervous system
exencephaly
(
J:57882
)
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• about 8% of pups from homozygous crosses display exencephaly
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reproductive system
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• about 50% of females fail to deliver their first litter resulting in death of the female
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neoplasm
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• following gamma irradiation tumor latency is decreased, frequency is increased, and most of the tumors are lymphomas of thymic origin
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renal/urinary system
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• diffuse global mesangial proliferation involving 40 - 100% of glomeruli is seen in older homozygotes
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• in some glomeruli
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• diffuse global mesangial proliferation involving 40 - 100% of glomeruli is seen in older homozygotes
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• 150 +/- 50 mg/dl of protein is seen in the urine of homozygous females suggesting chronic nephropathy
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• some glomeruli contain inflammatory cells, nuclear debris, and mesangial cell interposition, mild dilation of the proximal tubules occurs, and mild to severe dense perivascular mononuclear cell infiltrates are seen suggesting autoimmune glomerulonphritis
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• mild dilation of the proximal tubules
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homeostasis/metabolism
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• 150 +/- 50 mg/dl of protein is seen in the urine of homozygous females suggesting chronic nephropathy
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integument
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• in newborn and adult homozygous mice acute UVB-induced epidermal apoptosis, erythema, and induction of subcorneal pustules or epidermal erosion is reduced
• after UVB irradiation homozygous primary keratinocytes show an attenuated G1 arrest and a more pronounced reduction in G2 arrest compared to wild-type cells; however UVB-induced G1 and G2 arrest in dermal fibroblasts is similar to wild-type
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endocrine/exocrine glands
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• thymus weight as a percent of body weight is increased about 70% compared to wild-type
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• thymocyte number is increased but the distribution of thymocyte subpopulations is similar to wild-type
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| systemic lupus erythematosus | DOID:9074 |
OMIM:152700 OMIM:300809 OMIM:605480 OMIM:608437 OMIM:609903 OMIM:609939 OMIM:610065 OMIM:610066 OMIM:612254 OMIM:612378 OMIM:613145 OMIM:614420 |
J:76041 | |
