Regulation of Dendrite Growth by the Cdc42 Activator Zizimin1/Dock9 in Hippocampal Neurons
Regulation of Dendrite Growth by the Cdc42 Activator Zizimin1/Dock9 in Hippocampal Neurons
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DOI：
10.1002/jnr.21997
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发表时间：
2009-06-01
影响因子：
4.2
通讯作者：
Katoh, Hironori
中科院分区：
文献类型：
--
作者：
Kuramoto, Kazuya;Negishi, Manabu;Katoh, Hironori
Rho 家族小 GTP 酶是神经元形态变化的关键调节因子。 Cdc42 是 Rho 蛋白家族中最具特征的成员之一，通过细胞骨架重组参与轴突和树突的生长。最近的研究已确定 Zizimin1（Dock180 相关蛋白家族的成员 [也称为 CDM (Ced-5/Dock180/Myoblast city)-zizimin 同源 (CZH) 蛋白]）作为 Cdc42 的特定鸟嘌呤核苷酸交换因子 (GEF)。然而，Zizimin1的生理功能尚不清楚。在这项研究中，我们研究了 Zizimin1 在大鼠海马神经元树突发育中的作用。原位杂交和Western blot分析表明，Zizimin1在发育中的大脑中强烈表达，包括发育后期的海马体和大脑皮层。在原代培养的大鼠海马神经元中，野生型 Zizimin1 的过度表达促进树突生长，而通过短发夹 RNA 敲低 Zizimin1 或表达缺乏 Cdc42 GEF 活性的突变体 Zizimin1 则抑制树突生长。 CZH 蛋白中保守的 N 端 CZH1 结构域和 Zizimin1 的 Pleckstrin 同源结构域均参与膜定位、Cdc42 激活和树突生长调节。因此，这些结果表明 Zizimin1 通过激活 Cdc42 在海马神经元树突生长中发挥重要作用。 (C) 2009 Wiley-Liss, Inc.
Rho family small GTPases are key regulators of morphological changes in neurons. Cdc42, one of the most characterized members of the Rho family of proteins, is involved in axon and dendrite outgrowth through cytoskeletal reorganization. Recent studies have identified Zizimin1, a member of the Dock180-related family of proteins [also called CDM (Ced-5/Dock180/Myoblast city)-zizimin homology (CZH) proteins], as a specific guanine-nucleotide exchange factor (GEF) for Cdc42. However, the physiological function of Zizimin1 is totally unknown. In this study, we investigated the role of Zizimin1 in dendrite development in rat hippocampal neurons. In situ hybridization and Western blot analysis showed that Zizimin1 is strongly expressed in the developing brain including in the hippocampus and cerebral cortex in late developmental stages. Overexpression of wild-type Zizimin1 promoted dendrite growth, whereas knockdown of Zizimin1 by short hairpin RNA or expression of a mutant Zizimin1 lacking Cdc42 GEF activity suppressed dendrite growth in primary cultured rat hippocampal neurons. Both the N-terminal CZH1 domain, which is conserved among CZH proteins, and the Pleckstrin homology domain of Zizimin1 are involved in membrane localization, Cdc42 activation, and regulation of dendrite growth. Thus, these results suggest that Zizimin1 plays an important role in dendrite growth in hippocampal neurons through activation of Cdc42. (C) 2009 Wiley-Liss, Inc.