Regulating actin dynamics in neuronal growth cones by ADF/cofilin and rho family GTPases.

Journal of neurobiology Pub Date : 2000-08-01
T B Kuhn, P J Meberg, M D Brown, B W Bernstein, L S Minamide, J R Jensen, K Okada, E A Soda, J R Bamburg
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Abstract

Growth cone motility and navigation in response to extracellular signals are regulated by actin dynamics. To better understand actin involvement in these processes we determined how and in what form actin reaches growth cones, and once there, how actin assembly is regulated. A continuous supply of actin is maintained at the axon tip by slow transport, the mobile component consisting of an unassembled form of actin. Actin is co-transported with actin-binding proteins, including ADF and cofilin, structurally related proteins essential for rapid turnover of actin filaments in vivo. ADF and cofilin activity is regulated through phosphorylation by LIM kinases, downstream effectors of the Rho family of GTPases, Cdc42, Rac and Rho. Attractive and repulsive extracellular guidance cues might locally alter actin dynamics by binding specific GTPase-linked receptors, activating LIM kinases, and subsequently modulating the activity of ADF/cofilin. ADF is enriched in growth cones and is required for neurite outgrowth. In addition, signals that influence growth cone behavior alter ADF/cofilin phosphorylation, and overexpression of ADF enhances neurite outgrowth. Growth promoting effects of laminin are mimicked by expression of constitutively active Cdc42 and blocked by expression of the dominant negative Cdc42. Repulsive effects of myelin and sema3D on growth cones are blocked by expression of constitutively active Rac1 and dominant negative Rac1, respectively. Thus a series of complex pathways must exist for regulating effectors of actin dynamics. The bifurcating nature of the ADF/cofilin phosphorylation pathway may provide the integration necessary for this complex regulation.

ADF/cofilin和rho家族GTPases调控神经元生长锥内肌动蛋白动态。
生长锥的运动和导航响应细胞外信号是由肌动蛋白动力学调节的。为了更好地理解肌动蛋白在这些过程中的作用,我们确定了肌动蛋白是如何以及以什么形式到达生长锥的,以及一旦到达,肌动蛋白的组装是如何被调节的。肌动蛋白的持续供应是通过缓慢运输维持在轴突尖端的,肌动蛋白是由未组装形式的肌动蛋白组成的可移动成分。肌动蛋白与肌动蛋白结合蛋白共转运,包括ADF和cofilin,这两种结构相关蛋白在体内对肌动蛋白丝的快速周转至关重要。ADF和cofilin的活性是通过LIM激酶的磷酸化来调节的,LIM激酶是gtpase家族的下游效应物,Cdc42, Rac和Rho。吸引和排斥的细胞外引导线索可能通过结合特异性gtpase连接受体,激活LIM激酶,随后调节ADF/cofilin的活性来局部改变肌动蛋白动力学。ADF富含生长锥,是神经突生长所必需的。此外,影响生长锥行为的信号改变了ADF/cofilin的磷酸化,ADF的过表达增强了神经突的生长。层粘连蛋白的促生长作用通过表达组成型活性Cdc42来模拟,并通过表达显性负Cdc42来阻断。髓磷脂和sema3D对生长锥的排斥作用分别被组成型活性Rac1和显性阴性Rac1的表达所阻断。因此,肌动蛋白动力学效应因子的调控一定存在一系列复杂的通路。ADF/cofilin磷酸化途径的分叉性可能为这种复杂的调控提供了必要的整合。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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