Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice
Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice
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DOI：
10.1038/39601
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发表时间：
1997-10-16
期刊：
影响因子：
64.8
通讯作者：
Curran, T
中科院分区：
文献类型：
--
作者：
Sheldon, M;Rice, DS;Curran, T
哺乳动物大脑的形成需要神经元有计划地迁移以产生高度有序的层状结构，例如在前脑和小脑的皮质中的那些，这些过程被reelin(1)突变严重扰乱，这会导致Reeler鼠(2，3)中广泛的神经元错位和相关的共济失调(2，3)。Reelin是一种由先锋神经元分泌的大型细胞外蛋白，在神经发育过程中协调细胞定位(1，4-8)。已经描述了两个新的常染色体隐性小鼠突变，Scrbler(9)和yotari(10)，它们表现出与Reeler(9-11)相同的表型。在这里，我们报告了加扰器和yotari产生于mdab1(参考文献，12)的突变，这是一种与果蝇基因失活(Dab)(13)相关的小鼠基因。Sscbler和yotari小鼠都表达突变形式的mdab1信使RNA，很少或根本不表达mDab1蛋白。MDab1是一种磷酸化蛋白，在蛋白激酶途径中起着细胞内适配器的作用，表达分析表明，mdab1在暴露于Reelin的神经细胞中表达。Reeler、Scrbler、yotari和mdab1缺失小鼠(14)的相似表型表明，Reelin和mDab1作为信号分子发挥作用，调节发育中大脑中细胞的位置。
Formation of the mammalian brain requires choreographed migration of neurons to generate highly ordered laminar structures such as those in the cortices of the forebrain and the cerebellum, These processes are severely disrupted by mutations in reelin(1) which cause widespread misplacement of neurons and associated ataxia in reeler mice(2,3). Reelin is a large extracellular protein secreted by pioneer neurons that coordinates cell positioning during neurodevelopment(1,4-8). Two new autosomal recessive mouse mutations, scrambler(9) and yotari(10) have been described that exhibit a phenotype identical to reeler(9-11). Here we report that scrambler and yotari arise from mutations in mdab1 (ref, 12), a mouse gene related to the Drosophila gene disabled (dab)(13). Both scrambler and yotari mice express mutated forms of mdab1 messenger RNA and little or no mDab1 protein. mDab1 is a phosphoprotein that appears to function as an intracellular adaptor in protein kinase pathways, Expression analysis indicates that mdab1 is expressed in neuronal populations exposed to Reelin. The similar phenotypes of reeler, scrambler, yotari and mdab1 null mice(14) indicate that Reelin and mDab1 function as signalling molecules that regulate cell positioning in the developing brain.