Cell biological studies on the mechanisms of directed migration toward the pial surface from the cortical ventricular zone

精确调控的放射状细胞迁移出脑室区对于皮质生成是必不可少的。然而，控制迁移开始和迁移神经元细胞形状动态的分子机制仍然难以捉摸。然后，我们发现了可以束缚心室区细胞并控制迁移细胞形状的新机制（Nagano等人，Nat Cell Biol.，2002年）。新的蛋白细丝蛋白A相互作用蛋白（FILIP）与细丝蛋白A，一个不可缺少的肌动蛋白结合蛋白的细胞运动，并诱导其在COS-7细胞中的降解。细丝蛋白A的降解在FILIP mRNA定位的皮质心室区中指示。此外，大多数过度表达FILIP的心室区细胞在外植体中不能迁移。这些结果表明，FILIP通过细丝蛋白A-F-actin轴来控制新皮层细胞从脑室区迁移的开始。 ...更多信息 迁移的新皮层神经元的形状，在迁移过程中表现出全局性的形态变化和复杂的行为。由突变细丝蛋白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的过表达，实现了短干扰RNA的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，在进入皮质板和FILIP是负责，至少部分，细丝蛋白A的内容迁移neurons. Although这些结果，我们已经阐明的机制，控制细丝蛋白A的亚细胞定位。我们还研究了我们产生的FILIP基因敲除小鼠（仍在进行中）。少

Precisely regulated radial cell migration out of the ventricular zone is essential for corticogenesis. However, molecular mechanisms controlling the start of migration and the dynamics of migrating neuronal cell shape remain elusive. We then found novel mechanisms that can tether ventricular zone cells and control migrating cell shape (Nagano et al., Nat Cell Biol., 2002). The novel protein filamin A-interacting protein (FILIP) interacts with filamin A, an indispensable actin-binding protein for cell motility, and induces its degradation in COS-7 cells. Degradation of filamin A is indicated in the cortical ventricular zone where FILIP mRNA localizes. Furthermore, most ventricular zone cells that overexpress FILIP fail to migrate in explants. These results indicate that FILIP acts through a filamin A-F-actin axis to control the start of neocortical cell migration from the ventricular zone.In this study, we further examined the role of filamin A, then found that filamin A also determines … More the shape of migrating neocortical neurons, which show global morphological changes and complicated behavior during that migration. 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 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, prior to entering the cortical plate and that FILIP is responsible, at least in part, for the filamin A content of migrating neurons.In addition to these results, we have elucidated the mechanisms that control the subcellular localization of Filamin A. FILIP knockout mice that we generated were also studied (still in progress). Less