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

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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