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

神经丛蛋白是轴突导向分子信号素的受体。我们最近报道，Sema4D受体Plexin-B1在R-RAS/M-RAS之间起间隙作用，分别引起轴突和树突的排斥。我们研究了R-RAS/M-RAS的下游效应，与肌动蛋白细丝细胞骨架的调节有关，我们发现肌动蛋白聚合的调节剂lamellipdin(LPD)是R-RAS/M-RAS的一个新的效应器。R-RAS/M-RAS与LPD特异性结合并将其聚集到膜上，Sema4D/Plexin-B1抑制R-RAS/M-RAS活性和LPD膜转位，诱导海马神经元和皮质神经元中轴突和树突的排斥。我们的研究揭示了排斥性引导分子如何调节肌动蛋白细胞骨架，揭示了R-RAS/M-RAS-LPD系统通过SEMA/Plexin调节肌动蛋白轴突和树突重塑形成神经网络系统的新机制。

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.