Interaction of reelin signaling and Lis1 in brain development
Interaction of reelin signaling and Lis1 in brain development
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DOI：
10.1038/ng1257
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发表时间：
2003-11-01
期刊：
影响因子：
30.8
通讯作者：
Clark, GD
中科院分区：
文献类型：
--
作者：
Assadi, AH;Zhang, GC;Clark, GD
RELN（编码reelin蛋白）或PAFAH1B1（编码LIS1）的功能缺失突变会导致无脑回畸形，这是一种人类神经元迁移障碍。在小鼠中，Reln的纯合突变会导致reeler表型，其特征为共济失调和皮质层紊乱。Pafah1b1（+/-）小鼠有海马分层缺陷，而纯合突变体在胚胎期致死。Reln编码一种细胞外蛋白，它通过与极低密度脂蛋白受体（VLDLR）和载脂蛋白E受体2（ApoER2，即Lrp8）受体相互作用来调节层的形成，从而使Dab1信号分子磷酸化。Lis1与微管结合并调节神经元迁移。我们研究了reelin信号通路和Lis1在大脑发育过程中的相互作用。Reln通路被破坏且伴有Pafah1b1杂合突变的复合突变小鼠脑积水发生率更高，皮质和海马分层缺陷加剧。Dab1和Lis1以一种依赖于reelin诱导的磷酸化的方式结合。这些数据表明reelin信号通路和Lis1之间存在遗传和生化相互作用。
Loss-of-function mutations in RELN (encoding reelin) or PAFAH1B1 (encoding LIS1) cause lissencephaly, a human neuronal migration disorder(1). In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers(2). Pafah1b1(+/-) mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal(3). Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptors(4-6), thereby phosphorylating the Dab1 signaling molecule(7-10). Lis1 associates with microtubules and modulates neuronal migration(11). We investigated interactions between the reelin signaling pathway and Lis1 in brain development. Compound mutant mice with disruptions in the Reln pathway and heterozygous Pafah1b1 mutations had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. Dab1 and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicate genetic and biochemical interaction between the reelin signaling pathway and Lis1.