Filamin a and FILIP (Filamin A-interacting protein) regulate cell polarity and motility in neocortical subventricular and intermediate zones during radial migration
Filamin a and FILIP (Filamin A-interacting protein) regulate cell polarity and motility in neocortical subventricular and intermediate zones during radial migration
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DOI：
10.1523/jneurosci.2363-04.2004
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发表时间：
2004-10-27
影响因子：
5.3
通讯作者：
Sato, M
中科院分区：
文献类型：
--
作者：
Nagano, T;Morikubo, S;Sato, M
在发育中的新皮层中，大多数兴奋性神经元通过放射状迁移供应和排列。由于神经元在迁移过程中表现出全局性的形态变化和复杂的行为，因此精确调节细胞形状和极性对于正确的迁移和正确的新皮层形成是必不可少的;然而，在迁移的神经元中细胞形状和极性如何调节仍然是难以捉摸的。我们在这里表明，细丝蛋白A，一个众所周知的肌动蛋白结合蛋白，确定在体内放射状迁移过程中的新皮层神经元的形状。由突变体细丝蛋白A表达引起的细丝蛋白A功能障碍阻止细胞获得朝向特定方向的一致极性，并降低心室下区和中间区的运动性。相比之下，细丝蛋白A过表达，实现了一个短的干扰RNA的细丝蛋白A相互作用蛋白，诱导细丝蛋白A降解（FILIP），促进发展和维护的双极形状也在脑室下和中间区。这些结果表明，细丝蛋白A的量有助于迁移神经元确定其迁移模式，多极或双极，进入皮质板之前，菲利普负责，至少部分，细丝蛋白A的内容。此外，我们的研究结果也提供了一个可能的线索，以了解人类畸形室周异位，这是由各种“功能丧失”的细丝蛋白A基因突变。
In the developing neocortex, most excitatory neurons are supplied and arranged through radial migration. Because neurons show global morphological changes and complicated behavior during that migration, precise regulation of cell shape and polarity is essential for proper migration and correct neocortical formation; however, how cell shape and polarity are regulated in migrating neuron remains elusive. We show here that Filamin A, a well known actin-binding protein, determines the shape of neocortical neurons during radial migration in vivo. Dysfunction of Filamin A, caused by a mutant Filamin A expression, prevents cells from acquiring consistent polarity toward specific direction and decreases motility in the subventricular and intermediate zones. In contrast, Filamin A overexpression, achieved by a short interfering RNA for Filamin A-interacting protein that induces Filamin A degradation (FILIP), promotes the development and maintenance of a bipolar shape also in the subventricular and intermediate zones. These results suggest that the amount of Filamin A helps migrating neurons determine their mode of migration, multipolar or bipolar, before entering the cortical plate and that FILIP is responsible, at least in part, for Filamin A content. In addition, our results also give a possible clue to understanding the pathogenesis of human malformation periventricular heterotopia, which is caused by various "loss-of-function" mutations in the filamin A gene.