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，所谓的神经突生长，是神经元分化和成熟过程中神经系统发育过程中的关键事件。这些形态学的变化需要重组细胞骨架网络及其随附的膜扩张和收缩。 RAP1小G蛋白已通过调节MAP激酶（MAPK）级联反应和细胞骨架网络参与神经突生长和神经元极化。 Rho小G蛋白已通过调节肌动蛋白动力学参与神经元的形态发展。我们先前表明，诱导的神经突生长需要RHO失活。活化的Rho GTPase激活蛋白Ra-Rhogap将信号从RAP1转换为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的活性很重要。但是，如何和何处的RAP1的基础机制尚不清楚。在本研究项目中，我们确定Rap1，PDZ-GEF1的GDP/GTP交换因子（GEF）与这些事件有关。1）PC12细胞中GTP-RAP1在PC12细胞中被GTP-RAP1激活。 Rap1.3）在PC12细胞中，臂结合S型s型，它与PDZ-GEF1形成复合物，并募集了复合物至晚期内体。该晚期内体的这种四聚体复合物诱导Rap1和ERK的持续激活，导致神经突的生长。4）在培养的大鼠海马神经元中，轴突规范和伸长率参与了晚期内体的PDZ-GEF1 Tetramer复合体。