Roles of small GTPases in neuronal network formation

轴突引导是神经网络形成的关键阶段。轴突受多种引导因子的引导，如信号蛋白、ephrin、netrin等。神经丛蛋白的功能是作为反复性轴突引导分子，信号素的受体。我们发现信号素4D， Sema4D，受体Plexin-B1直接刺激R-Ras的内在GAPase活性，这已被证明通过激活整合素来促进神经突起的生长，以响应Sema4D。丛蛋白b1对R-Ras活性的下调是sema4d诱导海马神经元皱锥塌陷的必要条件。此外，sema3a诱导的生长锥塌陷也需要R-Ras活性的下调。因此，丛蛋白通过作为R-Ras的GAP介导信号素诱导的排斥信号。我们进一步表征了plexin - b1介导的R-Ras GAP活性的下游信号传导。Sema4D通过抑制R-Ras活性，抑制海马神经元中R-Ras活性，并使Akt和Akt去磷酸化。我们还发现Sema3A使Akt和GSK3去磷酸化。因此，Plexins使PI-3K和Akt失活，并通过R-Ras GAP活性激活GSK3，诱导生长锥坍塌。小gtpase的Rho家族与各种细胞的肌动蛋白细胞骨架重组和随后的形态变化有关。Rnd2是Rnd亚家族的成员，包括Rnd1、Rnd2和Rnd3。Rnd1和Rnd3对RhoA信号通路具有拮抗作用，而Rnd2的信号通路尚不清楚。我们使用Rnd2作为诱饵进行酵母双杂交筛选，并鉴定出一种新的Rnd2效应蛋白，主要在神经元中表达，包括皮质和海马神经元。我们把它命名为Pragmin。Pragmin刺激RhoA活性响应Rnd2，诱导细胞收缩和神经突收缩。因此，与Rnd1和Rnd3抑制RhoA信号传导相比，Rnd2通过Pragmin作为RhoA激活剂调节神经突起的生长。少

Axon guidance represents a key stage in the formation of neuronal network. Axons are guided by a variety of guidance factors, such as semaphorins, ephrins, and netrins. Plexins function as receptors for repylsive axonal guidance molecules, semaphorins. We have revealed that the semaphorin 4D, Sema4D, receptor Plexin-B1 directly stimulates the intrinsic GAPase activity of R-Ras, which has been shown to promote neurite outgrowth by activating integrins, in response to sema4D. The down regulation of R-Ras activity by the Plexin-B1 is essential for the Sema4D-induced frowth cone collapse in hippocampal neurons. In addition, the downregulation of R-Ras activity is also required for the Sema3A-induced growth cone collapse. Thus, Plexins mediate semaphorin-induced repulsive signaling by acting as a GAP for R-Ras. We have further characterized the downstream signaling of Plexin-B1-mediated R-Ras GAP activity. Sema4D suppressed R-Ras activity in hippocampal neurons and dephosphorylated Akt and … More GSK3 and phosphorylated CRMP-2, a microtubule polumerization stimulator, through its inhibition of R-Ras activity. We also found that Sema3A dephosphorylates Akt and GSK3. Therefore, Plexins inactivate PI-3K and Akt, and activate GSK3 through R-Ras GAP activity, inducing growth cone collapse.The Rho family of small GTPases has been implicated in the reorganization of actin cytoskeleton and subsequent morphological changes in various cells. Rnd2 is a member of the Rnd subfamily, comprising Rnd1, Rnd2, and Rnd3. In contrast to Rnd1 and Rnd3, displaying an antagonistic action for RhoA signaling, signaling pathways of Rnd2 are not well known. We have performed a yeast two-hybrid screen using Rnd2 as bait and identified a novel Rnd2 effector protein, predominantly expressed in neurons, including cortical and hippocampal neurons. We named it Pragmin. Pragmin stimulates RhoA activity in response to Rnd2, inducing cell contraction and neurite retraction. Therefore, Rnd2 regulates neurite outgrowth by functioning as the RhoA activator through Pragmin, in contrast to Rnd1 and Rnd3 inhibiting RhoA signaling. Less