Analysis Tools
mortality/aging
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• double homozygotes die by P18 or shortly thereafter as a result of developing neurologic deficits, indirect metabolic consequences, or both
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growth/size/body
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• at P18, double homozygotes appear consistently smaller than wild-type littermates
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weight loss
(
J:58522
)
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• double homozygotes develop normally until P14 but fail to thrive thereafter
• by P18, double homozygotes weigh significantly less than control littermates
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behavior/neurological
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• as early as P10, all double homozygotes start developing progressive neurological defects, eventually leading to paresis, bradykinesia, tremors, hypertonia, abnormal leg clasping reflexes, light sensitivity, and seizures
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• by P18, double homozygotes have trouble righting themselves
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limb grasping
(
J:58522
)
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• when lifted by their tails, double homozygotes hold their limbs by their trunk, whereas wild-type littermates twist, extend their legs, and attempt to find a solid object to grasp, including climbing back up their own tails
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bradykinesia
(
J:58522
)
respiratory system
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• by P18 or soon thereafter, all double homozygotes exhibit labored (Cheyne-Stokes) respiration
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nervous system
| N |
• double homozygotes display no gross alterations in brain histology or cytoarchitecture, suggesting that increased neuronal proliferation is balanced by cell death
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• at P18, double homozygotes show an increased number of pyknotic nuclei and positive apoptotic staining of neurons in layer II of the cortex and in the outer margins of the pyramidal layer of the hippocampus
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• at P18, double homozygotes exhibit increased proliferation of neurons not only in the corpus callosum but in many other parts of the brain, including the hippocampal pyramidal cell layer, layers III and V of the cerebral cortex, and the pontine and brainstem nuclei, all of which are normally quiescent at this age
• in addition, double homozygotes display ectopic neuronal proliferation in the hypothalamus, substantia nigra, and retina
• increased neuronal proliferation observed at P14 is counterbalanced by increased apoptotic cell death at P18
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muscle
homeostasis/metabolism
dehydration
(
J:58522
)
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• double homozygotes appear dehydrated prior to death
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• by P18, double homozygotes exhibit light sensitivity
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cellular
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• at P18, double homozygotes exhibit ectopic neuronal cell divisions in many brain regions, particularly within the pyramidal layer of the hippocampus
• on the basis of HH3 and NeuN staining, these neurons progress through G2 and M phase and undergo cytokinesis
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• on the basis of histone H3 staining (a marker for late G2 and M-phase progression), these neurons continue to divide after they have migrated to their final positions in the brain
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• at P18, double homozygotes show an increased number of pyknotic nuclei and positive apoptotic staining of neurons in layer II of the cortex and in the outer margins of the pyramidal layer of the hippocampus
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• metabolic labeling of live animals with BrdU at P14 and P18, combined with immunolabeling of neuronal markers, indicates that subpopulations of CNS differentiated neurons continue to proliferate in all parts of the brain, including normally dormant cells of the hippocampus, cortex, hypothalamus, pons, and brainstem
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vision/eye
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• by P18, double homozygotes exhibit light sensitivity
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