Formation of axon by vesicle transport and cytoskeltal rearrangement

通过囊泡运输和细胞骨架重排形成轴突

基本信息

批准号：
17590250
负责人：
SAKISAKA Toshiaki
金额：
$ 2.3万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590250/
关键词：
Formation of an axon Vesicle transport Rap1 small G protein PDZ-GEF1 C3G RA-RhoGAP 神経軸索伸長アクチン細胞骨格 Rho低分子量Gタンパク質ホスファチジン酸

项目摘要

Formation and extension of axons and dendrites, so-called neurite outgrowth, is a crucial event in neuronal differentiation and maturation during development of the nervous system. These morphological changes require reorganization of the cytoskeletal networks and its accompanying membrane expansion and contraction. Rap1 small G protein has been shown to be involved in neurite outgrowth and neuronal polarization through regulating the MAP kinase (MAPK) cascade and the cytoskeletal network. Rho small G protein has been shown to be involved in the morphological development of neurons through regulating actin dynamics. We previously showed that inactivation of Rho is required for the Induced-induced neurite outgrowth. Activated-activated Rho GTPase-activating protein, RA-RhoGAP, transduces a signal from Rap1 to Rho and inactivates Rho. The precise temporary and spatially activation of Rap1 is important for regulating the activity of RA-RhoGAP to produce the neurite. However, the mechanism underlying how and where Rap1 is activated remains unclear. In the present research project, we identified that a GDP/GTP exchange factor (GEF) for Rap1,PDZ-GEF1,was implicated in these events.1) PDZ-GEF1 was activated by GTP-Rap1 in a feedback mechanism.2) In PC12 cells, transport of nerve growth factor (NGF)-bound TrkA receptor to late endosomes is required for the NGF-induced sustained activation of Rap1.3) In PC12 cells, ARMS bound S-SCAM, which formed a complex with PDZ-GEF1, and recruited the complex to late endosomes. This tetramer complex at late endosomes induced sustained activation of Rap1 and ERK, resulting in neurite outgrowth.4) In cultured rat hippocampal neurons, the PDZ-GEF1 tetramer complex on late endosomes is involved in the axon specification and elongation.

轴突和树突的形成和延伸，即所谓的神经突生长，是神经系统发育过程中神经元分化和成熟的关键事件。这些形态变化需要细胞骨架网络的重组及其伴随的膜扩张和收缩。 Rap1 小 G 蛋白已被证明通过调节 MAP 激酶 (MAPK) 级联和细胞骨架网络参与神经突生长和神经元极化。 Rho 小 G 蛋白已被证明通过调节肌动蛋白动力学参与神经元的形态发育。我们之前表明，诱导神经突生长需要 Rho 失活。激活的 Rho GTP 酶激活蛋白 RA-RhoGAP 将信号从 Rap1 转导至 Rho 并使 Rho 失活。 Rap1 的精确临时和空间激活对于调节 RA-RhoGAP 的活性以产生神经突非常重要。然而，Rap1 如何以及在何处被激活的机制仍不清楚。在本研究项目中，我们发现 Rap1 的 GDP/GTP 交换因子 (GEF) PDZ-GEF1 与这些事件有关。1) PDZ-GEF1 在反馈机制中被 GTP-Rap1 激活。2) 在PC12 细胞中，NGF 诱导的 Rap1 持续激活需要将神经生长因子 (NGF) 结合的 TrkA 受体转运至晚期内体。3) 在 PC12 细胞中，ARMS 结合S-SCAM 与 PDZ-GEF1 形成复合物，并将该复合物招募到晚期内体。晚期内体上的这种四聚体复合物诱导 Rap1 和 ERK 持续激活，导致神经突生长。4) 在培养的大鼠海马神经元中，晚期内体上的 PDZ-GEF1 四聚体复合物参与轴突规范和伸长。