Institute for Biochemistry I, University Hospital Jena - Friedrich-Schiller-University Jena, Nonnenplan 2, 07743 Jena, Germany.
Eur J Cell Biol. 2011 Nov;90(11):926-33. doi: 10.1016/j.ejcb.2010.08.011. Epub 2010 Oct 20.
Coordinated functions of the actin cytoskeleton and microtubules, which need to be carefully controlled in time and space, are required for the drastic alterations of neuronal morphology during neuromorphogenesis and neuronal network formation. A key process in neuronal actin dynamics is filament formation by actin nucleators, such as the Arp2/3 complex, formins and the brain-enriched, novel WH2 domain-based nucleators Spire and cordon-bleu (Cobl). We here discuss in detail the currently available data on the roles of these actin nucleators during neuromorphogenesis and highlight how their required control at the plasma membrane may be brought about. The Arp2/3 complex was found to be especially important for proper growth cone translocation and axon development. The underlying molecular mechanisms for Arp2/3 complex activation at the neuronal plasma membrane include a recruitment and an activation of N-WASP by lipid- and F-actin-binding adaptor proteins, Cdc42 and phosphatidyl-inositol-(4,5)-bisphosphate (PIP(2)). Together, these components upstream of N-WASP and the Arp2/3 complex ensure fine-control of N-WASP-mediated Arp2/3 complex activation and control distinct functions during axon development. They are counteracted by Arp2/3 complex inhibitors, such as PICK, which likewise play an important role in neuromorphogenesis. In contrast to the crucial role of the Arp2/3 complex in proper axon development, dendrite formation and dendritic arborization was revealed to critically involve the newly identified actin nucleator Cobl. Cobl is a brain-enriched protein and uses three Wiskott-Aldrich syndrome protein homology 2 (WH2) domains for actin binding and for promoting the formation of non-bundled, unbranched filaments. Thus, cells use different actin nucleators to steer the complex remodeling processes underlying cell morphogenesis, the formation of cellular networks and the development of complex body plans.
在神经形态发生和神经元网络形成过程中，神经元形态发生发生剧烈变化，需要协调肌动蛋白细胞骨架和微管的功能，这需要在时间和空间上进行精细控制。神经元肌动蛋白动力学的一个关键过程是由肌动蛋白成核因子如 Arp2/3 复合物、formin 和富含脑的新型 WH2 结构域成核因子 Spire 和 cordon-bleu（Cobl）形成肌动蛋白丝。在这里，我们详细讨论了这些肌动蛋白成核因子在神经形态发生过程中的作用的现有数据，并强调了如何通过质膜来实现对它们的控制。Arp2/3 复合物对于正确的生长锥迁移和轴突发育尤为重要。神经元质膜上 Arp2/3 复合物的激活的潜在分子机制包括脂质和 F-肌动蛋白结合衔接蛋白、Cdc42 和磷脂酰肌醇-(4,5)-二磷酸（PIP(2)）对 N-WASP 的募集和激活。这些 N-WASP 和 Arp2/3 复合物上游成分共同确保了 N-WASP 介导的 Arp2/3 复合物激活的精细控制，并控制了轴突发育过程中的不同功能。它们被 Arp2/3 复合物抑制剂如 PICK 拮抗，PICK 在神经形态发生中也起着重要作用。与 Arp2/3 复合物在正确轴突发育中的关键作用相反，树突形成和树突分支被揭示严重依赖于新鉴定的肌动蛋白成核因子 Cobl。Cobl 是一种富含脑的蛋白质，它使用三个 Wiskott-Aldrich 综合征蛋白同源 2（WH2）结构域进行肌动蛋白结合并促进非束状、无分支丝的形成。因此，细胞使用不同的肌动蛋白成核因子来引导细胞形态发生、细胞网络形成和复杂身体计划发展的复杂重塑过程。
