Crystal structures of the F-BAR domains of FBP17, CIP4, and FCHo2 demonstrated that these domains are elongated homodimers characterized by a shallow curvature formed by the anti-parallel interaction of two alpha-helical coiled coils ( Henne et al., 2007 Shimada et al., 2007). The BAR-domain superfamily contains three main groups: the Bin/Amphiphysin/Rvs (BAR) domain subfamily ( Itoh and De Camilli, 2006), the Fes-Cip4 Homology (FCH)-BAR (also called F-BAR or EFC) domain subfamily (( Itoh et al., 2005 Tsujita et al., 2006) reviewed in ( Frost et al., 2009)) and the I-BAR subfamily (reviewed in ( Scita et al., 2008)). In particular, proteins containing Inverse-BAR (I-BAR) domain such as IRSp53, that induce membrane deformation have been shown to induce filopodia formation independent of its ability to bundle F-actin ( Lim et al., 2008 Mattila et al., 2007 Saarikangas et al., 2009). Interestingly, loss of ENA/VASP proteins also resulted in defects in cortical lamination ( Kwiatkowski et al., 2007) suggesting a functional relationship between filopodia formation, neurite initiation and neuronal migration.Ĭlassically, filopodia formation is thought to be primarily dependent on proteins that regulate actin polymerization at the barbed end of actin filaments and proteins bundling F-actin ( Gupton and Gertler, 2007). Downregulation of the actin anti-cappers, ENA/VASP proteins, which are potent inducers of filopodia resulted in failed neurite initiation. Filopodia have been shown to play a role in neurite initiation ( Dent et al., 2007 Kwiatkowski et al., 2007), growth cone dynamics ( Burnette et al., 2007 Gallo and Letourneau, 2004), neurite outgrowth ( Luo, 2002) and branching ( Dent et al., 2004 Gallo and Letourneau, 1998). The basis of neurite initiation, outgrowth and branching is rooted in the ability of the actin and microtubule cytoskeleton to undergo dynamic changes ( Gupton and Gertler, 2007 Luo, 2002 Mattila and Lappalainen, 2008). However, little is known about the molecular mechanisms underlying membrane dynamics during neuronal neuronal migration and morphogenesis. Recent genetic studies have identified regulators of leading process morphology and neuronal migration such as cyclin dependent kinase 5 (Cdk5) ( Ohshima et al., 2007) or its activator p35 ( Gupta et al., 2003). Cortical neuron migration involves the coordinated extension and adhesion of the leading process (LP) along radial glial processes with the forward translocation of the nucleus which requires regulation of centrosome and microtubule dynamics by proteins such as Lis1, Doublecortin, and Nudel among others ( Ayala et al., 2007 Higginbotham and Gleeson, 2007 Lambert de Rouvroit and Goffinet, 2001). These results (1) suggest that F-BAR domains are functionally diverse and (2) highlight the functional importance of proteins directly regulating membrane deformation for proper neuronal migration and morphogenesis.ĭuring brain development, neural progenitor proliferation, neuronal migration and differentiation require considerable changes in cell shape involving coordinated cytoskeletal and membrane remodeling ( Ayala et al., 2007 Luo, 2002). Overexpression of srGAP2 or its F-BAR domain has the opposite effects, increasing leading process branching and decreasing migration. srGAP2 knockdown reduces leading process branching and increases the rate of neuronal migration in vivo. Previous work has suggested that in non-neuronal cells, filopodia dynamics decreases the rate of cell migration and the persistence of leading edge protrusions. Here we report that srGAP2 negatively regulates neuronal migration and induces neurite outgrowth and branching through the ability of its F-BAR domain to induce filopodia-like membrane protrusions resembling those induced by I-BAR domains in vivo and in vitro. During brain development, proper neuronal migration and morphogenesis is critical for the establishment of functional neural circuits.
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