Elucidation of the Functional Roles of Rho GTPase-activating Proteins in Adult Neurogenesis

Adult hippocampal neurogenesis is the continuous generation of ne w neurons in the subgranular zone of dentate gyrus throughout life. It is regulated by both intrinsic and extrinsic signals. Dysfunctions of this process may lead to neurological disorders such as autism, epilepsy and schizophrenia. Rho GTPase -activating proteins (Rho-GAPs) are a family of regulatory proteins that bind to activated Rho GTPases, stimulating their GTPase activity. While Rho-GAPs regulate neuronal differentiation, neurite outgrowth, and migration during central nervous systemic development, whether they are important for the regulation of adult neurogenesis remains largely unknown. Accordingly, we investigated the role of a Rho-GAPα2-chimaerin in adult neurogenesis. We found that α2-chimaerin–knockout mice exhibited decreased adult hippocampal neurogenesis. In particular, the effect of α2-chimaerin was mediated through the regulation of neural progenitor cell proliferation, but not differentiation or maturation. Further study involving conditional knockout of α2-chimaerin showed a shift of the division mode of radial glia-like cells/neural progenitors from asymmetric to symmetric division. Furthermore, the dendritic development of adult-born neurons was attenuated in the α2-chimaerin–knockout dentate gyrus. These findings collectively indicate that the Rho-GAP α2-chimaerin is critical for adult hippocampal neurogenesis, suggesting it as a possible target for developing therapeutic treatment of neurological disorders.