Human Rho Guanine Nucleotide Exchange Factor 11 (ARHGEF11) Regulates Dendritic Morphogenesis.
Human Rho Guanine Nucleotide Exchange Factor 11 (ARHGEF11) Regulates Dendritic Morphogenesis.
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DOI：
10.3390/ijms18010067
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发表时间：
2016-12-29
影响因子：
5.6
通讯作者：
Yamada N
中科院分区：
文献类型：
--
作者：
Mizuki Y;Takaki M;Sakamoto S;Okamoto S;Kishimoto M;Okahisa Y;Itoh M;Yamada N
在围产期和青少年时期的突触连接的干扰已被假设为与精神分裂症的病理生理学。Rho鸟嘌呤核苷酸交换因子11（ARHGEF 11）是RhoA特异性的鸟嘌呤核苷酸交换因子（GEF），是肌动蛋白细胞骨架动力学和树突棘组织化的重要调节因子，也是树突棘维持的抑制因子。据报道，在日本人群中，ARHGEF 11变异与精神分裂症发作的高风险相关;然而，ARHGEF 11如何在树突棘中促进精神分裂症的发病机制尚不清楚。因此，我们首先研究了ARHGEF 11在大鼠大脑皮层树突棘中的分布、结合和功能。在大鼠大脑皮层的亚细胞分级分离后，在P2组分中用突触素和突触后密度蛋白95（PSD-95）检测ARHGEF 11，包括含有突触前和突触后密度蛋白的突触体组分。内源性ARHGEF 11与突触素或PSD-95共免疫沉淀。在体外培养28天的皮层原代神经元中，免疫染色显示ARHGEF 11位于树突和树突棘中，并与PSD-95和突触素共定位。外源性ARHGEF 11的过表达显著减少了棘的数量（p = 0.008）。这些结果表明，ARHGEF 11可能与突触膜和调节脊柱有关。
Disturbances of synaptic connectivity during perinatal and adolescent periods have been hypothesized to be related to the pathophysiology of schizophrenia. Rho guanine nucleotide exchange factor 11 (ARHGEF11) is a specific guanine nucleotide exchange factors (GEF) for RhoA, which is a critical regulator of actin cytoskeleton dynamics and organization of dendritic spines and inhibitor of spine maintenance. ARHGEF11 variants are reported to be associated with a higher risk for the onset of schizophrenia in a Japanese population; however, how ARHGEF11 contributes to the pathogenesis of schizophrenia in dendritic spines is unknown. Therefore, we first studied the distribution, binding, and function of ARHGEF11 in the dendritic spines of the rat cerebral cortex. After subcellular fractionation of the rat cerebral cortex, ARHGEF11 was detected with synaptophysin and post-synaptic density protein 95 (PSD-95) in the P2 fractions including synaptosomal fractions containing presynaptic and postsynaptic density proteins. Endogenous ARHGEF11 was coimmunoprecipitated with synaptophysin or PSD-95. In cortical primary neurons at 28 days in vitro, immunostaining revealed that ARHGEF11 located in the dendrites and dendritic spines and colocalized with PSD-95 and synaptophysin. Overexpression of exogenous ARHGEF11 significantly decreased the number of spines (p = 0.008). These results indicate that ARHGEF11 is likely to be associated with synaptic membranes and regulation of spine.