Multiple Dose-Dependent Effects ofLis1on Cerebral Cortical Development

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Abstract
Humans with heterozygous inactivating mutations of theLis1gene display type I lissencephaly, a severe form of cortical dysplasia hypothesized to result from abnormal neuronal migration. Previously we reported the construction of an allelic series of theLis1gene in mice to analyze the effects of graded reduction of LIS1 protein on the pathogenesis of this disorder and demonstrated a cell autonomous defect in neuronal migration (Hirotsune et al., 1998). Here we report the systematic examination of the consequences of dosage reduction of LIS1 on neocortical development using wild-type, null heterozygous (45% LIS1 protein), and compound null/hypomorphic (35% LIS1 protein) mice. The development of the preplate, Cajal-Retzius cells, and the radial glial scaffold appeared unaffected by LIS1 levels. However, a dose-dependent morphologic change in disorganization of the subplate was noted. LIS1 dose-dependent defects in neuronal migration were foundin vivoandin vitro. The position and number of mitotic cells in the ventricular zone were more abnormal as LIS1 levels decreased, suggesting defects in interkinetic nuclear migration and neuroblast proliferation. LIS1 dose-dependent progressive thinning of the cortex and ventricular zone occurred by programmed cell death. Thus, in addition to its requirement for cell autonomous neuronal migration, LIS1 influences the generation and survival of cortical ventricular zone neuroblasts. These studies reveal the importance of LIS1 levels in orderly cerebral cortical morphogenesis and suggest new insights into the pathogenesis of type I lissencephaly.