mortality/aging
• ~40% of mutant embryos die between E18.5 and birth, or shortly after
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• ~60% of mutant embryos die between E15.5 and E18.5
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muscle
• at E18.5, homozygotes exhibit absence of smaller secondary skeletal myofibers, suggesting a defect in secondary myogenesis which normally begins at ~E15
• however, in utero BrdU labeling indicates that secondary myoblast proliferation is normal at least through E15.5, suggesting a possible defect in the localized migration, alignment, or fusion of secondary myoblasts to form secondary myofibers
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• at E14.5, E16.5, and E18.5, homozygotes display abnormal skeletal muscle histology of the limb, trunk, and head, as shown in sagittal sections of thoracic paraspinal skeletal muscle and in coronal sections of the tongue muscle
• in contrast, the morphology of smooth and cardiac muscle appears unaffected
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• at E14.5, primary skeletal myofibers appear relatively normal but less organized than wild-type myofibers
• at E16.5, and esp. by E18.5, homozygotes exhibit abnormally large, thick, and spherical skeletal myofibers, and lack smaller secondary myofibers normally adjacent to the primary myofibers
• at E16.5 and E18.5, abnormal skeletal myofibers are multinucleated
• at E18.5, but not earlier, nuclei of atypical muscle fibers display poor H&E staining, indicating progressive degeneration of nuclei
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nervous system
• at E18.5, mutant embryos display abnormal positioning of a subset of neurons, as evidenced by localized areas of cellular disorganization in the dentate gyrus of the hippocampus and in the olfactory bulb
• however, overall brain development and gross histology appears normal
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• at E18.5, homozygotes display localized areas of cellular disorganization in the dentate gyrus
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• at E16.5 and E18.5, homozygotes display poor organization of the mitral cell layer in the olfactory bulbs
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cellular
• at E18.5, mutant embryos display abnormal positioning of a subset of neurons, as evidenced by localized areas of cellular disorganization in the dentate gyrus of the hippocampus and in the olfactory bulb
• however, overall brain development and gross histology appears normal
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