The Atypical Guanine Nucleotide Exchange Factor Dock4 Regulates Neurite Differentiation through Modulation of Rac1 GTPase and Actin Dynamics*
The Atypical Guanine Nucleotide Exchange Factor Dock4 Regulates Neurite Differentiation through Modulation of Rac1 GTPase and Actin Dynamics*
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DOI：
10.1074/jbc.m113.458612
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发表时间：
2013-05
期刊：
影响因子：
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通讯作者：
Yangui Xiao;Yinghui Peng;J. Wan;Genyun Tang;Yuewen Chen;Jing Tang;Wenqing Ye;N. Ip;Lei Shi
中科院分区：
文献类型：
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作者：
Yangui Xiao;Yinghui Peng;J. Wan;Genyun Tang;Yuewen Chen;Jing Tang;Wenqing Ye;N. Ip;Lei Shi
背景：DOCK4是一种针对rac1的鸟嘌呤核苷酸交换因子，与神经精神疾病有关。结果：DOCK4对神经母细胞瘤细胞和海马神经元的轴突分化有调节作用。结论：DOCK4是神经分化过程中的重要调节因子。意义：这项研究有助于更好地理解神经分化过程中的分子和细胞事件，并可能为神经精神疾病的分子病理生理学提供新的见解。对轴突生长和分化的精确调控决定了突触连接的准确形成，突触连接的中断经常与神经疾病有关。胞质分裂因子4(DOCK4)是一种非典型的rac1鸟嘌呤核苷酸交换因子，被发现与包括自闭症和精神分裂症在内的神经精神疾病有关。尽管如此，DOCK4的神经功能才刚刚开始被了解。以小鼠神经母细胞瘤(Neuro-2a)细胞为模型，本研究发现DOCK4对神经突起的分化和延伸至关重要。这种调节是通过激活rac1和调节突起上肌动蛋白丰富的突起的动力学来实现的。在培养的海马神经元中，DOCK4调节轴突-树突极性的建立和树突的树枝形成，这是神经分化过程中的两个关键过程。重要的是，与自闭症和阅读障碍相关的DOCK4微缺失突变体缺乏gef结构域，会导致轴突生长缺陷和神经元极化。进一步的分析表明，DOCK4的SH3结构域介导的相互作用是其向轴突分化所必需的，而其富含Pro的C末端并不是这种调控所必需的。综上所述，我们的发现揭示了DOCK4在神经元早期发育过程中对轴突分化的重要作用。
Background: Dock4, a guanine nucleotide exchange factor for Rac1, is associated with neuropsychiatric diseases. Results: Dock4 regulates neurite differentiation in neuroblastoma cells and hippocampal neurons. Conclusion: Dock4 is an important regulator during neural differentiation. Significance: This study contributes to a better understanding of the molecular and cellular events during neural differentiation and may provide new insights into the molecular pathophysiology of neuropsychiatric diseases. Precise regulation of neurite growth and differentiation determines accurate formation of synaptic connections, whose disruptions are frequently associated with neurological disorders. Dedicator of cytokinesis 4 (Dock4), an atypical guanine nucleotide exchange factor for Rac1, is found to be associated with neuropsychiatric diseases, including autism and schizophrenia. Nonetheless, the neuronal function of Dock4 is only beginning to be understood. Using mouse neuroblastoma (Neuro-2a) cells as a model, this study identifies that Dock4 is critical for neurite differentiation and extension. This regulation is through activation of Rac1 and modulation of the dynamics of actin-enriched protrusions on the neurites. In cultured hippocampal neurons, Dock4 regulates the establishment of the axon-dendrite polarity and the arborization of dendrites, two critical processes during neural differentiation. Importantly, a microdeletion Dock4 mutant linked to autism and dyslexia that lacks the GEF domain leads to defective neurite outgrowth and neuronal polarization. Further analysis reveals that the SH3 domain-mediated interaction of Dock4 is required for its activity toward neurite differentiation, whereas its proline-rich C terminus is not essential for this regulation. Together, our findings reveal an important role of Dock4 for neurite differentiation during early neuronal development.