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Phenotypes Associated with This Genotype
Genotype
MGI:6163827
Allelic
Composition
Pole4tm1(KOMP)Vlcg/Pole4tm1(KOMP)Vlcg
Genetic
Background
involves: 129S1/Sv * 129X1/SvJ * C57BL/6NTac * FVB/N
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Pole4tm1(KOMP)Vlcg mutation (0 available); any Pole4 mutation (4 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• embryos die between E13.5 and birth; only 9.3% of homozygotes are born versus expected 25%

growth/size/body
• bulging forehead at E15.5
• embryos are significantly smaller at E13.5
• significantly lower body weight from 3 to 34 weeks postpartum
• significantly shorter body length from 3 to 34 weeks postpartum
• fetuses are significantly smaller at E15.5
• at E13.5, mice show intrauterine growth retardation with no apparent developmental abnormalities

embryo
• at E13.5, embryos show significantly increased apoptosis (p53 and cleaved caspase 3 staining) and DNA damage (as shown by gamma-H2AX staining) in the forebrain and liver
• embryos are significantly smaller at E13.5
• at E13.5, embryos show lengthening of the roof plate, resulting in defective midline fusion

craniofacial
• >80% mice exhibit craniofacial abnormalities
• significantly smaller mandible length relative to femur length at E15.5
• however, skull size is normal
• bulging forehead at E15.5

skeleton
• significantly smaller mandible length relative to femur length at E15.5
• however, skull size is normal
• significantly smaller tibia length relative to femur length at E15.5
• however, humerus and radius size is normal
• tail kinks or curls are caused by vertebrae fusions
• significantly smaller pelvis length relative to femur length at E15.5

behavior/neurological
• ataxic phenotype does not worsen with age
• at 3 months of age, mice fall around 3 s earlier from the rotating rod than wild-type controls
• 70%-80% mice show an unusual gait

hematopoietic system
• ~80% of mice exhibit absent or a structurally disorganized thymus
• thymi are devoid of cortex and are composed of medulla only structures, suggesting that T cell maturation is severely impaired
• in some cases
• B cells tend to stay at an immature IgD-negative stage
• mice show a 20-fold increase in the number of CD4- CD8- double-negative precursor cells relative to wild-type controls
• mice show moderate anemia
• mice show a 2.3-fold reduction in the number of white blood cells relative to wild-type controls
• lymphopenia is associated with an increase in the proportion of granulocytes and monocytes
• mice show an 8-fold reduction in the number of B cells relative to wild-type controls
• mice show a 5-fold decrease of CD4+ and CD8+ T lymphocytes relative to wild-type controls
• long-term (LT-HSC, CD34- Flt3-) and short-term (ST-HSC, CD34+ Flt3-) HSCs are decreased
• mice show a 3.5-fold increase in the number of LSK (Lin-Sca1+cKit+) cells in the bone marrow relative to wild-type controls
• the number of multipotent progenitors (MPPs, CD34+Flt3+) is increased by ~2-fold
• spleen is smaller than normal
• spleen to body weight is lower than normal
• >30% of mice exhibit spleens with inconspicuous and/or underdeveloped follicles, suggesting impaired B cell maturation

immune system
• ~80% of mice exhibit absent or a structurally disorganized thymus
• thymi are devoid of cortex and are composed of medulla only structures, suggesting that T cell maturation is severely impaired
• in some cases
• B cells tend to stay at an immature IgD-negative stage
• mice show a 20-fold increase in the number of CD4- CD8- double-negative precursor cells relative to wild-type controls
• mice show a 2.3-fold reduction in the number of white blood cells relative to wild-type controls
• lymphopenia is associated with an increase in the proportion of granulocytes and monocytes
• mice show an 8-fold reduction in the number of B cells relative to wild-type controls
• mice show a 5-fold decrease of CD4+ and CD8+ T lymphocytes relative to wild-type controls
• spleen is smaller than normal
• spleen to body weight is lower than normal
• >30% of mice exhibit spleens with inconspicuous and/or underdeveloped follicles, suggesting impaired B cell maturation
• mesenteric lymph nodes have a disorganized structure with underdeveloped follicles

nervous system
• at E13.5, embryos show significantly increased apoptosis (p53 and cleaved caspase 3 staining) and DNA damage (as shown by gamma-H2AX staining) in the forebrain
• at E13.5, embryos show lengthening of the roof plate, resulting in defective midline fusion
• at 3 months of age, only 3-6 lobules are observed in the cerebellum versus 7-10 lobules in wild-type controls
• adult brain weight is significantly lower than in wild-type controls
• however, ratio between whole body and brain size is relatively normal
• at E13.5, the roof of the fourth ventricle is expanded
• at 3 months of age, cerebellum size is reduced

neoplasm
• mice show an increased incidence of lymphomas in the mesenteric lymph nodes (23.5% versus 7.7% in wild-type controls)
• mice show an increased incidence of lymphomas in the thymus (~12% versus 4% in wild-type controls)

cellular
• marked reduction in the number of pro-myelocytic leukemia zinc-finger (PLZF)-positive cells per testis tubule in P5 testes
• MEFs exhibit increased levels of the replicative stress markers 53BP1 and gamma-H2AX
• MEFs exhibit increased fork rates and larger inter-origin distances associated with accumulation of fork stalling events
• EdU/DAPI flow cytometry revealed an increased proportion of MEFs in the G2 phase of the cell cycle
• at E13.5, embryos show significantly increased apoptosis (p53 and cleaved caspase 3 staining) and DNA damage (as shown by gamma-H2AX staining) in the forebrain and liver
• at E13.5, embryos show significantly increased apoptosis (p53 and cleaved caspase 3 staining) and DNA damage (as shown by gamma-H2AX staining) in the forebrain
• MEFs are not sensitive to ionizing radiation (IR) but show heightened sensitivity to hydroxyurea (HU) relative to wild-type cells
• MEFs exhibit showed higher IOD (inter-origin distance) values when challenged with HU, consistent with inefficient origin activation upon replication stress
• mouse embryonic fibroblasts (MEFs) show reduced proliferative potential under a standard 3T3 protocol and in low-oxygen (5%) conditions
• MEFs exhibit polymerase (DNA directed) epsilon (Pole) complex instability, leading to inefficient origin activation, replicative stress, genome instability, and p53 activation
• following treatment with a low aphidicolin dose, MEFs show a dramatic increase in the frequency of chromosome breaks and rearrangements

homeostasis/metabolism
• MEFs exhibit increased levels of the replicative stress markers 53BP1 and gamma-H2AX
• MEFs exhibit increased fork rates and larger inter-origin distances associated with accumulation of fork stalling events

endocrine/exocrine glands
• ~80% of mice exhibit absent or a structurally disorganized thymus
• thymi are devoid of cortex and are composed of medulla only structures, suggesting that T cell maturation is severely impaired
• in some cases
• mice show an increased incidence of lymphomas in the thymus (~12% versus 4% in wild-type controls)

integument
• ~25% of mice exhibit white patches on the belly

reproductive system
• marked reduction in the number of pro-myelocytic leukemia zinc-finger (PLZF)-positive cells per testis tubule in P5 testes
• breeding involving one homozygote in a pair produced only 15 litters with 118 pups (0.95 litters per 21-day-gestation interval and 7.5 pups per litter)
• mice are subfertile, producing significantly less litters with a tendency for fewer pups per litter

limbs/digits/tail
• significantly smaller tibia length relative to femur length at E15.5
• however, humerus and radius size is normal
• tail kinks or curls are caused by vertebrae fusions
• 5%-10% mice exhibit curls in their tails
• ~60% of mice exhibit kinks in their tails

pigmentation
• ~25% of mice exhibit white patches on the belly


Contributing Projects:
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
08/13/2019
MGI 6.14
The Jackson Laboratory