Regulation of axon guidance and dendritic spine development by Vav family GEFs

The complicated process of brain circuit assembly occurs via a series of integrated steps. It begins with cell type specification and neuronal migration, which are then followed by axon guidance and synapse development. This dissertation focuses on the latter two processes, first studying how Vav family of guanine nucleotide exchange factors (GEFs) determine the navigation choices of the axons, and then examining the potential roles of Vav proteins in the morphogenesis of the postsynaptic compartments. Axon guidance is typically mediated by guidance cue-receptor interactions on the surface of axonal growth cones. Although substantial progress has been made at the ligand/receptor level, relatively little is known about how activated guidance receptors orchestrate the complex signaling processes that lead to the reorganization of the cytoskeleton and eventually growth cone turning. We identified the Vav family GEFs as a critical mediator of Eph receptor-dependent axon guidance. Ephrin binding to Ephs triggers Vav-dependent endocytosis of the ligand-receptor complex, thus converting an initially adhesive interaction into a repulsive event. In the absence of Vav proteins, ephrin-Eph endocytosis is blocked, leading to defects in growth cone collapse in vitro and significant defects in the ipsilateral retinogeniculate projections in vivo . These findings suggest an important role for Vav family GEFs as regulators of ligand-receptor endocytosis and determinants of repulsive signaling during axon guidance. Dendritic spines function as the postsynaptic component for the majority of the excitatory synapses in the brain. Spine formation and remodeling, which underlie synaptic development and plasticity, are tightly regulated by surface receptors and intracellular signaling pathways. Here, we report that Vav2 is localized postsynaptically in the dendritic spines. Overexpressing a dominant interfering form of Vav2 in rat organotypic hippocampal slices leads to an increase in spine density of the CA3/CA1 pyramidal neurons. This is further confirmed by examining pyramidal cells from Vav1-/Vav2-/-Vav3-/- hippocampal slices. Interestingly, preliminary results indicate that, CA3 pyramidal neurons might be preferentially affected in the Vav mutant animals, compared to CA1 neurons. These findings suggest that Vav family GEFs play an important role in restricting dendritic spine morphogenesis in vivo .