Rho-GTPase-activating Protein Interacting with Cdc-42-interacting Protein 4 Homolog 2 (Rich2) A NEW Ras-RELATED C3 BOTULINUM TOXIN SUBSTRATE 1 (Rac1) GTPase-ACTIVATING PROTEIN THAT CONTROLS DENDRITIC SPINE MORPHOGENESIS
Rho-GTPase-activating Protein Interacting with Cdc-42-interacting Protein 4 Homolog 2 (Rich2) A NEW Ras-RELATED C3 BOTULINUM TOXIN SUBSTRATE 1 (Rac1) GTPase-ACTIVATING PROTEIN THAT CONTROLS DENDRITIC SPINE MORPHOGENESIS
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DOI：
10.1074/jbc.m113.534636
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发表时间：
2014-01-31
影响因子：
4.8
通讯作者：
Fagni, Laurent
中科院分区：
文献类型：
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作者：
Raynaud, Fabrice;Moutin, Enora;Fagni, Laurent
背景：RICH2是一种突触Rho-GAP(Rho-GTP酶激活蛋白)，其作用靶点不明。结果：我们发现Rich2通过抑制rac1的活性来控制树突棘的形态发生。结论：在脊柱中，rac1是Rich2的靶标。意义：我们首次发现Rich2是一种在脊柱形成中起重要作用的rac1-GAP蛋白。树突棘的发育对突触功能非常重要，脊柱形态发生的改变通常与精神障碍有关。RICH2是一个未知的Rho-GAP蛋白。在这里，我们寻找这种蛋白在脊柱形态发生中的作用。我们发现，在发育的早期阶段，它在培养的海马锥体神经元的树突棘中丰富。Rich2特异性地刺激这些神经元中的rac1 GTP酶。EHT1864对rac1的抑制作用使树突棘的大小增加，密度降低。同样，Rich2过表达增加了树突棘的大小，降低了树突棘的密度，而通过特定的si-RNA敲除该蛋白则减少了树突棘的大小和密度。Rich2过表达引起的微小EPSCs的幅度增加和频率降低反映了细胞的形态变化，而si-RNA处理使这些事件的幅度和频率都降低了。最后，用EHT1864处理神经元，挽救了Rich2基因敲除所诱导的表型。这些结果表明，Rich2通过抑制rac1调控树突棘的形态发生和功能。
Background: Rich2 is a synaptic Rho-GAP (Rho-GTPase-activating protein) the target of which was unknown. Results: We found that Rich2 controls dendritic spine morphogenesis by inhibiting Rac1 activity. Conclusion: Rac1 is the target of Rich2 in spines. Significance: We identified for the first time Rich2 as a Rac1-GAP protein that plays an important role in spine formation.Development of dendritic spines is important for synaptic function, and alteration in spine morphogenesis is often associated with mental disorders. Rich2 was an uncharacterized Rho-GAP protein. Here we searched for a role of this protein in spine morphogenesis. We found that it is enriched in dendritic spines of cultured hippocampal pyramidal neurons during early stages of development. Rich2 specifically stimulated the Rac1 GTPase in these neurons. Inhibition of Rac1 by EHT 1864 increased the size and decreased the density of dendritic spines. Similarly, Rich2 overexpression increased the size and decreased the density of dendritic spines, whereas knock-down of the protein by specific si-RNA decreased both size and density of spines. The morphological changes were reflected by the increased amplitude and decreased frequency of miniature EPSCs induced by Rich2 overexpression, while si-RNA treatment decreased both amplitude and frequency of these events. Finally, treatment of neurons with EHT 1864 rescued the phenotype induced by Rich2 knock-down. These results suggested that Rich2 controls dendritic spine morphogenesis and function via inhibition of Rac1.