Semaphorin 4D/Plexin-B1-Mediated M-Ras GAP Activity Regulates Actin-Based Dendrite Remodeling through Lamellipodin
Semaphorin 4D/Plexin-B1-Mediated M-Ras GAP Activity Regulates Actin-Based Dendrite Remodeling through Lamellipodin
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DOI：
10.1523/jneurosci.0799-12.2012
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发表时间：
2012-06-13
影响因子：
5.3
通讯作者：
Oinuma, Izumi
中科院分区：
文献类型：
--
作者：
Tasaka, Gen-ichi;Negishi, Manabu;Oinuma, Izumi
信号蛋白被认为是发育中的神经系统的排斥性引导分子。我们最近报道了信号蛋白4D （Sema4D）受体Plexin-B1在轴突和树突中分别作为gtpase激活蛋白（GAP）作用于R-Ras和M-Ras，从而诱导排斥。在轴突中，Sema4D刺激可诱导生长锥塌陷，这一作用需要plexin - b1介导的GAP活性下调R-Ras活性。轴突R-Ras GAP活性下调磷脂酰肌醇3-激酶信号通路，从而诱导微管组装启动子蛋白CRMP-2失活。然而，与信号蛋白和丛蛋白在轴突引导中的作用相比，连接M-Ras GAP和树突状细胞骨架的信号分子仍然不清楚。在这里，我们发现了一种Ena/VASP配体，Lamellipodin (Lpd)，作为树突中M-Ras的新效应体。Lpd在富含f -actin的远端树突中表达，是基础和m - ras介导的树突发育所必需的。亚细胞分离显示Lpd依赖于m - ras的膜易位，Sema4D抑制了这种易位。此外，Lpd内的Ena/ vasp结合区是树突发育所必需的，其膜靶向性足以克服sema4d介导的树突生长减少和远端树突f -肌动蛋白的消失。此外，子宫内电穿孔实验也表明，丛蛋白的GAP活性对M-Ras-Lpd系统的调节参与了体内皮层树突的正常发育。总的来说，我们的研究揭示了排斥性引导分子如何调节树突中的肌动蛋白细胞骨架，揭示了M-Ras-Lpd系统通过Sema/丛蛋白调节大鼠或小鼠基于肌动蛋白的树突重塑的新机制。
Semaphorins have been identified as repulsive guidance molecules in the developing nervous system. We recently reported that the semaphorin 4D (Sema4D) receptor Plexin-B1 induces repulsion in axon and dendrites by functioning as a GTPase-activating protein (GAP) for R-Ras and M-Ras, respectively. In axons, Sema4D stimulation induces growth cone collapse, and downregulation of R-Ras activity by Plexin-B1-mediated GAP activity is required for the action. Axonal R-Ras GAP activity downregulates phosphatidylinositol 3-kinase signaling pathway, and thereby induces inactivation of a microtubule assembly promoter protein, CRMP-2. However, in contrast to the well studied roles of semaphorins and plexins in axonal guidance, signaling molecules linking M-Ras GAP to dendritic cytoskeleton remain obscure. Here we identified an Ena/VASP ligand, Lamellipodin (Lpd), as a novel effector of M-Ras in dendrites. Lpd was expressed in F-actin-rich distal dendritic processes and was required for both basal and M-Ras-mediated dendrite development. Subcellular fractionation showed M-Ras-dependent membrane translocation of Lpd, which was suppressed by Sema4D. Furthermore, the Ena/VASP-binding region within Lpd was required for dendrite development, and its membrane targeting was sufficient to overcome the Sema4D-mediated reduction of dendritic outgrowth and disappearance of F-actin from distal dendrites. Furthermore, in utero electroporation experiments also indicated that regulation of the M-Ras-Lpd system by the GAP activity of Plexin is involved in the normal development of cortical dendrites in vivo. Overall, our study sheds light on how repulsive guidance molecules regulate actin cytoskeleton in dendrites, revealing a novel mechanism that the M-Ras-Lpd system regulates actin-based dendrite remodeling by Sema/Plexin in rats or mice of either sex.