Semaphorin 3A activates the guanosine triphosphatase Rab5 to promote growth cone collapse and organize callosal axon projections.
Semaphorin 3A activates the guanosine triphosphatase Rab5 to promote growth cone collapse and organize callosal axon projections.
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Semaphorin 3A 激活鸟苷三磷酸酶 Rab5，促进生长锥塌陷并组织胼胝体轴突投射。
DOI：
10.1126/scisignal.2005334
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发表时间：
2014-08-26
影响因子：
7.3
通讯作者：
Luo ZG
中科院分区：
文献类型：
--
作者：
Wu KY;He M;Hou QQ;Sheng AL;Yuan L;Liu F;Liu WW;Li G;Jiang XY;Luo ZG
轴突引导（寻路）在发育过程中连接大脑，并受到各种吸引和排斥线索的调节。Semaphorin 3A（Sema 3A）是一种排斥性因子，诱导轴突生长锥的塌陷。在哺乳动物前脑中，胼胝体是两个半球之间传递信息流的主要连合，对侧轴突组装成明确的神经束。我们发现，图案化的胼胝体轴突投射在啮齿动物层II和III（L2/3）皮层神经元在响应Sema 3A介导的Rab 5，一个小的鸟苷三磷酸酶（GTdR）介导的内吞作用，通过膜融合蛋白Rabaptin-5和Rab 5鸟嘌呤核苷酸交换因子（GEF）Rabex-5的激活。Rabaptin-5在Sema 3A受体复合物中直接与丛蛋白-A1结合[丛蛋白-A1和神经纤毛蛋白1（NP 1）形成的专性异二聚体]; Sema 3A在培养的神经元中增强了这种相互作用。Rabaptin-5是Rab 5与丛蛋白A1相互作用的桥梁。Sema 3A刺激胼胝体轴突生长锥细胞表面的内吞作用。在子宫内电穿孔，以减少Rab 5或Rabaptin-5受损的轴突成束或引起L2/3胼胝体投射的错误。Rabaptin-5或Rab 5的过表达挽救了由表达显性阴性丛蛋白-A1的大鼠或NP 1缺陷小鼠中的Sema 3A-丛蛋白-A1信号传导丧失引起的有缺陷的胼胝体轴突成束或胼胝体轴突的错误启动。因此，我们的研究结果表明，Rab 5，其效应Rabaptin-5，其调节Rabex-5介导Sema 3A诱导的轴突在大脑发育过程中的指导。
Axon guidance (pathfinding) wires the brain during development and is regulated by various attractive and repulsive cues. Semaphorin 3A (Sema3A) is a repulsive cue, inducing the collapse of axon growth cones. In the mammalian forebrain, the corpus callosum is the major commissure that transmits information flow between the two hemispheres, and contralateral axons assemble into well-defined tracts. We found that the patterning of callosal axon projections in rodent layer II and III (L2/3) cortical neurons in response to Sema3A was mediated by the activation of Rab5, a small guanosine triphosphatase (GTPase) that mediates endocytosis, through the membrane fusion protein Rabaptin-5 and the Rab5 guanine nucleotide exchange factor (GEF) Rabex-5. Rabaptin-5 bound directly to Plexin-A1 in the Sema3A receptor complex [an obligate heterodimer formed by Plexin-A1 and neuropilin 1 (NP1)]; Sema3A enhanced this interaction in cultured neurons. Rabaptin-5 bridged the interaction between Rab5 and Plexin-A1. Sema3A stimulated endocytosis from the cell surface of callosal axon growth cones. In utero electroporation to reduce Rab5 or Rabaptin-5 impaired axon fasciculation or caused mistargeting of L2/3 callosal projections in rats. Over-expression of Rabaptin-5 or Rab5 rescued the defective callosal axon fasciculation or mistargeting of callosal axons caused by the loss of Sema3A–Plexin-A1 signaling in rats expressing dominant-negative Plexin-A1 or in NP1-deficient mice. Thus, our findings suggest that Rab5, its effector Rabaptin-5, and its regulator Rabex-5 mediate Sema3A-induced axon guidance during brain development.