Isolated lissencephaly (ILS) is a human brain developmental disorder in which the brain has a smooth cerebral surface and disorganized cortical layers due to abnormal neuronal migration. ILS is often associated with haploinsufficiency at chromosome 17p13, or with heterozygous mutations in LIS1, a subunit of platelet activating factor acetylhydrolase. To dissect the molecular mechanisms responsible for these defects, we created a mouse model of lissencephaly by targeted disruption of Lis1 in the mouse. Heterozygous Lis1 mutant mice were viable and fertile. However, as in ILS human patients, hemizyous Lis1 mutants displayed neuronal migration abnormalities. The brains of chimeric mice derived from Lis1 targeted ES cells also displayed a mosaic pattern of disorganization suggesting that the abnormal neuronal cell migration resulting from hemizygous loss of Lis1 function is cell autonomous. Homozygous Lis1 disruption resulted in embryonic lethality, prior to 9.5 days post conception, demonstrating an essential role for Lis1 in early embryonic developmental events. Thus, Lis1 mutant mice provide an excellent model for human lissencephaly, and will provide a tool to elucidate the molecular mechanisms responsible for the neuronal migration defects seen in ILS patients. In addition, Lis1 is essential for murine embryonic development.
