Analysis Tools
mortality/aging
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• no homozygous mutant embryos are identified after E16
• notably, transfer of a human retinoblastoma mini-transgene rescues the lethal phenotype; homozygotes harboring multiple copies of this mini-transgene are viable and some reach the age of 6 months displaying no obvious neuronal or hematopoietic system defects
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nervous system
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• at E11.5, homozygotes display massive neuronal apoptosis throughout the CNS, esp. in the hindbrain region; telencephalic structures and caudal spinal cord are less affected
• at E12.5, mutant embryos show extensive cell death in the intermediate zone and maturing neuronal centers; the ventricular zone of the spinal cord appears relatively unaffected
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• although most brain regions develop on time, the cytoarchitecture of mutant brains is distorted
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• in homozygotes, the overall size of the developing brain is reduced relative to wild-type
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• by E12.5, many homozygotes have an enlarged fourth ventricle
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• at E13.5, the spinal cord and spinal ganglia of mutant embryos exhibit ectopic mitosis and neuronal cell death; as a result, the size of mutant spinal ganglia is markedly reduced by E15.5
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• as early as E11.5, mutant dorsal root ganglia exhibit extensive cell death; by 15.5, these ganglia are reduced to small sheath-like structures
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hematopoietic system
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• at E14.5 and at E15.5, many of the nucleated erythrocytes in mutant embryos show aberrant morphology and staining
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• although hepatic hematopoiesis occurs in mutant embryos, most of the erythrocytes are of the less mature, nucleated type
• in E12.5 mutant embryos, ~75% of the total erythrocyte population in peripheral blood is nucleated as in wild-type embryos; however, nucleated erythrocytes still present 65% of the population at E13.5, 70% at E14.5 and 50% at E15.5, suggesting deregulated proliferation of mutant primitive erythrocytes
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liver/biliary system
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• at E14.5 and at E15.5, mutant livers display enlarged sinusoids relative to wild-type
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• at E14.5 and at E15.5, mutant livers have fewer hepatocytes relative to wild-type
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small liver
(
J:2516
)
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• at E14.5 and at E15.5, the mutant liver is smaller but hematopoietic islands are clearly identifiable
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embryo
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• homozygotes appear morphologically normal up to E10.5
• notably, by E11.5, ~30% of mutant embryos appear developmentally abnormal relative to wild-type; the time of onset of abnormalities varies over a 2-3 day period
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growth/size/body
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• all homozygotes become runted by E14.0
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cardiovascular system
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• by E13.5, many homozygotes are pale with poor blood distribution
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• at E14.5 and at E15.5, mutant livers display enlarged sinusoids relative to wild-type
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homeostasis/metabolism
skeleton
cellular
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• at E11.5, homozygotes display massive neuronal apoptosis throughout the CNS, esp. in the hindbrain region; telencephalic structures and caudal spinal cord are less affected
• at E12.5, mutant embryos show extensive cell death in the intermediate zone and maturing neuronal centers; the ventricular zone of the spinal cord appears relatively unaffected
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• at E12.5, homozygotes display abundant mitotic figures in CNS regions normally reserved for neuronal migration or differentiation (e.g. the ventricular zone and intermediate zone of the spinal cord)
• ectopic cells divisions are also detected in the developing inferior olive, which appears wider and less organized; however, no significant cell death is observed concomitant with a 30% increase in the number of migrating cells
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vision/eye
| N |
• surprisingly, mutant retinas display normal size and cytoarchitecture relative to wild-type
• no signs of cell loss are observed in the developing neural retinas up to E15.5
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