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The function of Reggie (and PrP) in cargo trafficking underlying axon growth, regeneration and synapse formation

Reggie（和 PrP）在轴突生长、再生和突触形成的货物运输中的功能

基本信息

批准号：
229733047
负责人：
Professorin Dr. Claudia Stürmer
金额：
--
依托单位：
Arbeitsgruppe Neurobiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/229733047?language=en
关键词：
function Reggie PrP cargo trafficking

项目摘要

The microdomain proteins reggie-1 and -2 are essential for axon growth and their upregulation promotes regeneration of fish and mammalian retinal ganglion cell axons in vivo. This is causally linked with the ability of reggies to coordinate - together with the cellular prion protein (PrP) - the recruitment of N-cadherin to the growth cone of hippocampal neurons, of E-cadherin to adherens junctions of epithelial cell contact sites and of the T cell receptor to the T cell cap. Our current concept explains how reggie (and PrP) support such diverse functions: they participate in the turnover and targeted delivery of membrane proteins in a cell type specific manner. This implies that reggie (and PrP) regulate cargo trafficking and recycling, which is consistent with the observation that reggie (and PrP) in Hela cells associate with a tubulo-vesicular transport system which is Rab11, Arf6, EHD-1 and sorting nexin (SNX)4-positive, depends on the intact microtubule and actin cytoskeleton and contains E-cadherin as cargo. In order to understand how reggie (and PrP) control cargo supply to growing axons and support regeneration we will analyse the interaction of reggie (and PrP) with GTPases (Rab11, Arf6, TC10) and membrane scaffolding proteins (of the SNX and EHD families) with functions in cargo sorting and trafficking. A function of reggie in trafficking suggests that reggie (together with PrP) participates in the formation and regulation of spine synapses and the recruitment of N-cadherin, glutamate AMPA and NMDA receptor subunits. Our results will elucidate a novel sorting and recycling pathway which depends on reggies (and PrP) and which is essential for neuronal differentiation, synapse formation and repair.

reggie-1和reggie-2是轴突生长所必需的微结构域蛋白，它们的上调促进了体内鱼类和哺乳动物视网膜神经节细胞轴突的再生。这与reggies与细胞朊蛋白（PrP）一起协调N-钙粘蛋白向海马神经元生长锥的募集、E-钙粘蛋白向上皮细胞接触部位的粘附连接的募集以及T细胞受体向T细胞帽的募集的能力有因果关系。我们目前的概念解释了reggie（和PrP）如何支持这些不同的功能：它们以细胞类型特异性的方式参与膜蛋白的周转和靶向递送。这意味着reggie（和PrP）调节货物运输和再循环，这与Hela细胞中的reggie（和PrP）与Rab 11，Arf 6，EHD-1和分选连接蛋白（SNX）4阳性的小管-囊泡运输系统相关的观察结果一致，依赖于完整的微管和肌动蛋白细胞骨架，并含有E-钙粘蛋白作为货物。为了了解reggie（和PrP）如何控制货物供应到生长的轴突并支持再生，我们将分析reggie（和PrP）与GTP酶（Rab 11，Arf 6，TC 10）和膜支架蛋白（SNX和EHD家族）的相互作用，这些蛋白具有货物分选和运输功能。Reggie在运输中的功能表明，Reggie（与PrP一起）参与脊柱突触的形成和调节以及N-钙粘蛋白、谷氨酸AMPA和NMDA受体亚基的募集。我们的研究结果将阐明一个新的排序和回收途径，这取决于reggies（和PrP），这是必不可少的神经元分化，突触形成和修复。