Lissencephaly is a severe brain malformation in humans. To study the function of the gene mutated in lissencephaly (LIS1), we deleted the first coding exon from the mouse Lis1 gene. The deletion resulted in a shorter protein (sLIS1) that initiates from the second methionine, a unique situation because most LIS1 mutations result in a null allele. This mutation mimics a mutation described in one lissencephaly patient with a milder phenotype. Homozygotes are early lethal, although heterozygotes are viable and fertile. Most strikingly, the morphology of cortical neurons and radial glia is aberrant in the developing cortex, and the neurons migrate more slowly. This is the first demonstration, to our knowledge, of a cellular abnormality in the migrating neurons after Lis1 mutation. Moreover, cortical plate splitting and thalomocortical innervation are also abnormal. Biochemically, the mutant protein is not capable of dimerization, and enzymatic activity is elevated in the embryos, thus a demonstration of the in vivo role of LIS1 as a subunit of PAF-AH. This mutation allows us to determine a hierarchy of functions that are sensitive to LIS1 dosage, thus promoting our understanding of the role of LIS1 in the developing cortex.brain development ͉ lissencephaly ͉ platelet-activating factor ͉ acetylhydrolase ͉ gene targeting L IS1 was identified as the gene mutated in a severe human developmental brain malformation known as lissencephaly (''smooth brain'') type I (1). Patients with lissencephaly often are severely retarded, epileptic, and die at a young age. The most striking feature of the brains of affected individuals is that they are smooth and largely devoid of the sulci and gyri that characterize the normal brain. The lissencephalic brain exhibits defects in neuronal migration that result in poor organization of cortical layering. A reduced surface area and lack of cortical folds are also seen, possibly because of an overall reduced number of neurons (2). Mutations in two different genes may result in type I lissencephaly: LIS1, an autosomal gene located on chromosome 17p13.3 (1), and doublecortin, an X-linked gene (3, 4). The pattern of expression of LIS1 in the nervous system suggested that the mouse would be a suitable organism for studying the role of LIS1 during brain development (5). Mouse embryos homozygous for the null Lis1 allele (Lis1Ϫ͞Ϫ) die after implantation, whereas heterozygotes are viable and fertile (6). A half dosage of LIS1 affects neuronal migration only slightly in the developing cortex, whereas adult layer organization appears normal. Further gene dosage reduction severely obstructs cortical and hippocampal organization (6). LIS1 interacts with many proteins and is involved in several basic cellular functions, including mitosis, nuclear positioning, and microtubule regulation (for review, see ref. 7). To better understand the function of LIS1 and its role in neuronal migration, we produced Lis1 mutant mice by using cre recombinase-mediated loxP deletion. Our mutation resulted in a shorter LIS1 p...
