F-BAR Proteins of the Syndapin Family Shape the Plasma Membrane and Are Crucial for Neuromorphogenesis
F-BAR Proteins of the Syndapin Family Shape the Plasma Membrane and Are Crucial for Neuromorphogenesis
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DOI：
10.1523/jneurosci.3973-09.2009
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发表时间：
2009-10-21
影响因子：
5.3
通讯作者：
Qualmann, Britta
中科院分区：
文献类型：
--
作者：
Dharmalingam, Elavarasi;Haeckel, Akvile;Qualmann, Britta
在神经形态发生和神经元网络形成过程中，肌动蛋白细胞骨架和微管的协调功能对于神经元形态的剧烈变化是必不可少的，这需要在时间和空间上进行仔细的控制。由Arp2/3复合体及其激活的神经Wiskott-Aldrich综合征蛋白(N-WASP)驱动的肌动蛋白细丝的形成对轴突的正常发育至关重要。然而，到目前为止，N-WASP靶向神经细胞质膜和在神经细胞膜上特异性激活的潜在分子机制仍然难以捉摸。我们证明Syndapin I对于正常的神经形态发生是关键的，因此使用N-WASP作为细胞骨架效应器。当N-WASP结合时，Syndapins释放N-WASP自身抑制。Syndapins在此与CdC42和磷脂酰肌醇-(4，5)-二磷酸合作。Syndapins还通过其扩展的F-bar结构域与含有磷脂酰丝氨酸的膜特异性结合。通过对Syndapin在体内的肌动蛋白成核和直接膜结合功能的剖析，我们证明了这两种功能在生理上是相关的和必需的。体内结构性质膜靶向实验表明，突触素触发了细胞皮质肌动蛋白的特异性成核。与Syndapins引导N-WASP作为皮质肌动蛋白成核的下游效应器一致，Syndapin诱导的神经元树枝形成是N-WASP和CDC42依赖的。功能丧失研究揭示了突触素-N-WASP复合体在神经形态发生中的作用。突触素I的敲除导致轴突发育受损，尤其是在N-WASP和Arp2/3复合体缺乏时观察到的异常轴突分支。相反，适当的长度控制涉及另一种N-WASP结合蛋白Abp1。因此，我们的数据表明，突触素I对神经形态发生至关重要，不同的N-WASP激动剂确保了对N-WASP活性的精细控制，并在神经元网络形成过程中具有不同的功能。
Coordinated functions of the actin cytoskeleton and microtubules, which require careful control in time and space, are indispensable for the drastic alterations of neuronal morphology during neuromorphogenesis and neuronal network formation. Actin filament formation driven by the Arp2/3 complex and its activator neural Wiskott-Aldrich syndrome protein (N-WASP) is important for proper axon development. The underlying molecular mechanisms for targeting to and specific activation of N-WASP at the neuronal plasma membrane, however, have thus far remained elusive. We show that syndapin I is critical for proper neuromorphogenesis and hereby uses N-WASP as a cytoskeletal effector. Upon N-WASP binding, syndapins release N-WASP autoinhibition. Syndapins hereby cooperate with Cdc42 and phosphatidyl-inositol-(4,5)-bisphosphate. Syndapins furthermore specifically bind to phosphatidylserine-containing membranes via their extended F-BAR domain. Dissecting the syndapin functions actin nucleation and direct membrane binding in vivo, we demonstrate that both functions are physiologically relevant and required. Constitutive plasma membrane-targeting experiments in vivo indicate that specifically actin nucleation at the cell cortex is triggered by syndapins. Consistent with syndapins steering N-WASP as downstream effector for cortical actin nucleation, syndapin-induced neuronal arborization is N-WASP and Cdc42 dependent. The functions of syndapin-N-WASP complexes in neuromorphogenesis were revealed by loss-of-function studies. Knockdown of syndapin I leads to impaired axon development and especially phenocopies the aberrant axon branching observed upon N-WASP and Arp2/3 complex deficiency. In contrast, proper length control involves another N-WASP-binding protein, Abp1. Our data thus reveal that syndapin I is crucial for neuromorphogenesis and that different N-WASP activators ensure fine control of N-WASP activity and have distinct functions during neuronal network formation.