Roles of signaling systems of small GTPases in the formation of neural network system

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Plexins are receptors for axonal guidance molecules semaphorins. We recently reported that the Sema4D receptor, Plexin-B1, functions as a GAP for R-Ras/M-Ras, inducing repulsion of both axons and dendrites, respectively. We have examined downstream effectors of R-Ras/M-Ras, linking to regulation of actin filament cytoskeleton, and we identified lamellipodin (lpd), a regulator of actin polymerization, as a novel effector of R-Ras/M-Ras. R-Ras/M-Ras specifically bind to lpd and recruite it to membranes, and Sema4D/Plexin-B1 suppresses R-Ras/M-Ras activity and lpd membrane translocation, inducing repulsion of axons and dendrite in hippocampal and cortical neurons. Our study shed light on how repulsive guidance molecules regulate actin cytoskeleton, revealing a novel mechanism that the R-Ras/M-Ras-lpd systems regulate actin-based axon and dendrite remodeling by sema/plexin in the formation of neural network system.