Roles of small GTPases in neuronal network formation

小 GTP 酶在神经元网络形成中的作用

基本信息

批准号：
16390021
负责人：
NEGISHI Manabu
金额：
$ 9.47万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390021/
关键词：
semaphorin plexin Rnd Rho axon neurite R-Ras GAP semaphorin PhoG ELMO Dock180 神経突起 R-Ras RhoG Rnd1 神経回路成長円錐

项目摘要

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

轴突指导代表了神经元网络形成的关键阶段。轴突以各种引导因素为指导，例如闪光蛋白，以弗林蛋白和网状蛋白。丛蛋白充当复制性轴突引导分子的受体，信号素。我们已经透露，Sema4d，SemA4D，受体plexin-B1直接刺激R-RAS的固有间隙酶活性，R-RAS已被证明可通过激活整合素来促进神经蛋白的生长，以响应SEMA4D。 Plexin-B1对R-RAS活性的下降对于海马神经元中SEMA4D诱导的弗洛斯锥塌陷至关重要。另外，SEMA3A诱导的生长锥塌陷也需要RAS活性的下调。这是丛集素中位数信号素诱导的排斥信号传导，通过充当R-RAS的差距。我们进一步表征了Plexin-B1介导的R-RAS间隙活性的下游信号传导。 SEMA4D通过抑制R-RAS活性的抑制了Microtubule致化刺激剂，抑制了海马神经元和去磷酸化的AKT和…更多GSK3和磷酸化CRMP-2的RAS活性。我们还发现SEMA3A脱磷酸化AKT和GSK3。因此，丛蛋白使PI-3K和AKT失活，并通过R-RAS间隙活性激活GSK3，诱导生长锥崩溃。 RND2是RND亚家族的成员，完成了RND1，RND2和RND3。与RND1和RND3相反，显示了用于RhoA信号传导的拮抗作用，RND2的信号传导途径尚不清楚。我们使用RND2作为诱饵进行了酵母两杂化筛选，并确定了一种新型的RND2效应蛋白，主要在神经元中表达，包括皮质和海马神经元。我们将其命名为Pragmin。 pragmin刺激RND2刺激RhoA活性，从而诱导细胞收缩和神经落回收。因此，与RND1和RND3抑制RHOA信号相比，RND2通过将RND2通过Pragmin充当RhoA激活剂来调节神经元的生长。较少的