GRIP1 controls dendrite morphogenesis by regulating EphB receptor trafficking
GRIP1 controls dendrite morphogenesis by regulating EphB receptor trafficking
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DOI：
10.1038/nn1487
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发表时间：
2005-07-01
影响因子：
25
通讯作者：
Sheng, M
中科院分区：
文献类型：
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作者：
Hoogenraad, CC;Milstein, AD;Sheng, M
多PDZ结构域支架蛋白GRIP1(谷氨酸受体相互作用蛋白1)在神经元中的功能尚不清楚。为了探讨GRIP1在海马神经元中的功能，我们利用RNA干扰技术(RNAi)下调了GRIP1的表达。在培养的海马神经元中，小干扰RNA(SiRNA)下调GRIP1导致树突的丢失，与GRIP相互作用的蛋白质GluR2(AMPA受体亚单位)、EphB2(受体酪氨酸激酶)和KIF5(也称为kinesin 1；微管运动)的错误定位有关。GRIP1-siRNA可通过EphB2胞外区的过表达来挽救树突状细胞的缺失，并通过EphB2胞内区的过表达和ewitinB-Fc融合蛋白的胞外应用来弥补树突状细胞的缺失。EphB1-EphB2-EphB3三基因敲除小鼠的神经元表现出异常的树突形态发生。KIF5-GRIP1相互作用的中断抑制了EphB2的运输，并强烈损害了树突状细胞的生长。这些结果表明，GRIP1在树突状细胞形态发生中起重要作用，它作为依赖于动蛋白的EphB受体转运到树突状细胞的适配蛋白。
The function of the multi-PDZ domain scaffold protein GRIP1 (glutamate receptor interacting protein 1) in neurons is unclear. To explore the function of GRIP1 in hippocampal neurons, we used RNA interference (RNAi) to knock down the expression of GRIP1. Knockdown of GRIP1 by small interfering RNA (siRNA) in cultured hippocampal neurons caused a loss of dendrites, associated with mislocalization of the GRIP-interacting proteins GluR2 (AMPA receptor subunit), EphB2 (receptor tyrosine kinase) and KIF5 (also known as kinesin 1; microtubule motor). The loss of dendrites by GRIP1-siRNA was rescued by overexpression of the extracellular domain of EphB2, and was phenocopied by overexpression of the intracellular domain of EphB2 and extracellular application of ephrinB-Fc fusion proteins. Neurons from EphB1-EphB2-EphB3 triple knockout mice showed abnormal dendrite morphogenesis. Disruption of the KIF5-GRIP1 interaction inhibited EphB2 trafficking and strongly impaired dendritic growth. These results indicate an important role for GRIP1 in dendrite morphogenesis by serving as an adaptor protein for kinesin-dependent transport of EphB receptors to dendrites.