Analysis Tools
mortality/aging
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• embryos die between E13.5 and birth; only 9.3% of homozygotes are born versus expected 25%
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growth/size/body
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• bulging forehead at E15.5
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• embryos are significantly smaller at E13.5
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• at E13.5
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• significantly lower body weight from 3 to 34 weeks postpartum
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• significantly shorter body length from 3 to 34 weeks postpartum
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• fetuses are significantly smaller at E15.5
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• at E15.5
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• at E13.5, mice show intrauterine growth retardation with no apparent developmental abnormalities
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embryo
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• 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
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• embryos are significantly smaller at E13.5
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• at E13.5
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• at E13.5, embryos show lengthening of the roof plate, resulting in defective midline fusion
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craniofacial
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• >80% mice exhibit craniofacial abnormalities
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• significantly smaller mandible length relative to femur length at E15.5
• however, skull size is normal
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• bulging forehead at E15.5
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skeleton
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• significantly smaller mandible length relative to femur length at E15.5
• however, skull size is normal
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short tibia
(
J:261973
)
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• significantly smaller tibia length relative to femur length at E15.5
• however, humerus and radius size is normal
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• tail kinks or curls are caused by vertebrae fusions
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• significantly smaller pelvis length relative to femur length at E15.5
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behavior/neurological
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• at 3 months of age, mice fall around 3 s earlier from the rotating rod than wild-type controls
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• 70%-80% mice show an unusual gait
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hematopoietic system
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• ~80% of mice exhibit absent or a structurally disorganized thymus
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• thymi are devoid of cortex and are composed of medulla only structures, suggesting that T cell maturation is severely impaired
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• mice show an increased incidence of lymphomas in the thymus (~12% versus 4% in wild-type controls)
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• B cells tend to stay at an immature IgD-negative stage
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• mice show a 20-fold increase in the number of CD4- CD8- double-negative precursor cells relative to wild-type controls
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• mice show a 2.3-fold reduction in the number of white blood cells relative to wild-type controls
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• lymphopenia is associated with an increase in the proportion of granulocytes and monocytes
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• mice show an 8-fold reduction in the number of B cells relative to wild-type controls
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• mice show a 5-fold decrease of CD4+ and CD8+ T lymphocytes relative to wild-type controls
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• long-term (LT-HSC, CD34- Flt3-) and short-term (ST-HSC, CD34+ Flt3-) HSCs are decreased
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• 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
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small spleen
(
J:261973
)
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• spleen is smaller than normal
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• spleen to body weight is lower than normal
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• >30% of mice exhibit spleens with inconspicuous and/or underdeveloped follicles, suggesting impaired B cell maturation
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immune system
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• ~80% of mice exhibit absent or a structurally disorganized thymus
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• thymi are devoid of cortex and are composed of medulla only structures, suggesting that T cell maturation is severely impaired
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• mice show an increased incidence of lymphomas in the thymus (~12% versus 4% in wild-type controls)
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• B cells tend to stay at an immature IgD-negative stage
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• mice show a 20-fold increase in the number of CD4- CD8- double-negative precursor cells relative to wild-type controls
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• mice show a 2.3-fold reduction in the number of white blood cells relative to wild-type controls
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• lymphopenia is associated with an increase in the proportion of granulocytes and monocytes
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• mice show an 8-fold reduction in the number of B cells relative to wild-type controls
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• mice show a 5-fold decrease of CD4+ and CD8+ T lymphocytes relative to wild-type controls
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small spleen
(
J:261973
)
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• spleen is smaller than normal
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• spleen to body weight is lower than normal
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• >30% of mice exhibit spleens with inconspicuous and/or underdeveloped follicles, suggesting impaired B cell maturation
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• mesenteric lymph nodes have a disorganized structure with underdeveloped follicles
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nervous system
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• 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
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• at E13.5, embryos show lengthening of the roof plate, resulting in defective midline fusion
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• at 3 months of age, only 3-6 lobules are observed in the cerebellum versus 7-10 lobules in wild-type controls
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• adult brain weight is significantly lower than in wild-type controls
• however, ratio between whole body and brain size is relatively normal
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• at E13.5, the roof of the fourth ventricle is expanded
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• at 3 months of age, cerebellum size is reduced
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neoplasm
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• mice show an increased incidence of lymphomas in the mesenteric lymph nodes (23.5% versus 7.7% in wild-type controls)
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• mice show an increased incidence of lymphomas in the thymus (~12% versus 4% in wild-type controls)
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cellular
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• marked reduction in the number of pro-myelocytic leukemia zinc-finger (PLZF)-positive cells per testis tubule in P5 testes
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• EdU/DAPI flow cytometry revealed an increased proportion of MEFs in the G2 phase of the cell cycle
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• 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
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• 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
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• 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
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• mouse embryonic fibroblasts (MEFs) show reduced proliferative potential under a standard 3T3 protocol and in low-oxygen (5%) conditions
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• 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
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• MEFs exhibit polymerase (DNA directed) epsilon (Pole) complex instability, leading to inefficient origin activation, replicative stress, genome instability, and p53 activation
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• following treatment with a low aphidicolin dose, MEFs show a dramatic increase in the frequency of chromosome breaks and rearrangements
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homeostasis/metabolism
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• 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
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endocrine/exocrine glands
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• ~80% of mice exhibit absent or a structurally disorganized thymus
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• thymi are devoid of cortex and are composed of medulla only structures, suggesting that T cell maturation is severely impaired
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• mice show an increased incidence of lymphomas in the thymus (~12% versus 4% in wild-type controls)
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integument
belly spot
(
J:261973
)
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• ~25% of mice exhibit white patches on the belly
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reproductive system
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• marked reduction in the number of pro-myelocytic leukemia zinc-finger (PLZF)-positive cells per testis tubule in P5 testes
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• mice are subfertile, producing significantly less litters with a tendency for fewer pups per litter
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• 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)
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limbs/digits/tail
short tibia
(
J:261973
)
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• significantly smaller tibia length relative to femur length at E15.5
• however, humerus and radius size is normal
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• tail kinks or curls are caused by vertebrae fusions
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curly tail
(
J:261973
)
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• 5%-10% mice exhibit curls in their tails
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kinked tail
(
J:261973
)
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• ~60% of mice exhibit kinks in their tails
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pigmentation
belly spot
(
J:261973
)
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• ~25% of mice exhibit white patches on the belly
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