Cahana A, Escamez T, Nowakowski R S, Hayes N L, Giacobini M, von Holst A, Shmueli O, Sapir T, McConnell S K, Wurst W, Martinez S, Reiner O
Department of Molecular Genetics, Weizmann Institute of Science, 76100 Rehovot, Israel.
Proc Natl Acad Sci U S A. 2001 May 22;98(11):6429-34. doi: 10.1073/pnas.101122598. Epub 2001 May 8.
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.
无脑回畸形是人类一种严重的脑畸形。为了研究在无脑回畸形中发生突变的基因（LIS1）的功能，我们从小鼠Lis1基因中删除了第一个编码外显子。这种缺失导致了一种从第二个甲硫氨酸起始的较短蛋白质（sLIS1），这是一种独特的情况，因为大多数LIS1突变会导致无效等位基因。这种突变模拟了一名具有较轻微表型的无脑回畸形患者中描述的一种突变。纯合子在早期致死，而异合子是存活且可育的。最显著的是，在发育中的皮质中，皮质神经元和放射状胶质细胞的形态异常，并且神经元迁移更慢。据我们所知，这是首次证明Lis1突变后迁移神经元中存在细胞异常。此外，皮质板分裂和丘脑皮质神经支配也异常。在生化方面，突变蛋白不能二聚化，并且胚胎中的酶活性升高，从而证明了LIS1作为血小板激活因子乙酰水解酶（PAF-AH）亚基在体内的作用。这种突变使我们能够确定对LIS1剂量敏感的功能层次，从而增进我们对LIS1在发育中的皮质中作用的理解。
