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

精确调节径向细胞向心室区外的迁移对皮质发生至关重要。然而，控制迁移开始的分子机制和迁移神经元细胞形状的动力学仍然是难以捉摸的。然后我们发现了新的机制，可以拴住心室区细胞和控制迁移细胞的形状（Nagano等人，Nat cell Biol）。, 2002)。在COS-7细胞中，新型蛋白filamin A相互作用蛋白（FILIP）与细胞运动不可或缺的肌动蛋白结合蛋白filamin A相互作用，并诱导其降解。FILIP mRNA所在的皮质心室区显示丝蛋白A的降解。此外，大多数过表达FILIP的心室区细胞在外植体中无法迁移。这些结果表明FILIP通过丝蛋白a - f -肌动蛋白轴来控制新皮质细胞从心室区迁移的开始。在本研究中，我们进一步研究了丝蛋白A的作用，发现丝蛋白A还决定了迁移的新皮层神经元的形状，这些神经元在迁移过程中表现出全局的形态变化和复杂的行为。由丝蛋白A表达突变引起的丝蛋白A功能障碍，阻止细胞在特定方向上获得一致的极性，并降低心室下和中间区的运动性。相反，丝蛋白A的过表达，通过FILIP的短干扰RNA实现，也促进了心室下和中间区双极形状的发展和维持。这些结果表明，丝蛋白A的数量有助于迁移神经元在进入皮质板之前确定其迁移模式，多极或双极，并且FILIP至少部分地负责迁移神经元的丝蛋白A含量。除了这些结果，我们还阐明了控制Filamin A.亚细胞定位的机制，我们也研究了我们产生的FILIP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