Identification of CRMP4 as a convergent regulator of axon outgrowth inhibition
Identification of CRMP4 as a convergent regulator of axon outgrowth inhibition
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DOI：
10.1523/jneurosci.5055-06.2007
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发表时间：
2007-02-14
影响因子：
5.3
通讯作者：
Fournier, Alyson E.
中科院分区：
文献类型：
--
作者：
Alabed, Yazan Z.;Pool, Madeline;Fournier, Alyson E.
髓磷脂相关抑制剂（MAI）和硫酸软骨素蛋白聚糖（CSPGS）在神经元损伤后导致再生失败。 MAI和CSPG刺激细胞内信号，包括RhoA和Rho激酶的激活，通过针对细胞骨架的靶向修饰来阻断轴突延伸。 Rhoa和Rock是治疗干预以促进中枢神经系统修复的有前途的目标。但是，它们无处不在的表达将限制针对这些分子的药物的特异性。我们已经将胞质磷酸蛋白CRMP4B（折叠蛋白反应介质蛋白4B）鉴定为一种蛋白质，在物理和功能上与RhoA相互作用以介导神经突生长抑制。简短的干扰RNA介导的CRMP4敲低可促进髓磷脂底物上的神经突生长，这表明CRMP4B神经突生长抑制作用至关重要。与竞争性抑制剂的CRMP4B-RHOA结合破坏了对髓磷脂和Aggrecan底物的神经突生长的抑制作用。用NOGO刺激神经元生长锥导致在肌动蛋白丰富的中心和周围的生长锥的离散区域的CRMP4B和RHOA共定位，这表明神经突生长抑制过程中细胞骨架重排的潜在功能。总之，这些数据表明，RHOA-CRMP4B复合物响应生长锥环境中的抑制挑战，并调节轴突生长抑制所需的不同位点的细胞骨架动力学。 CRMP4B-RHOA结合的竞争性抑制作用表明了一种新型的，高度特异性的治疗途径，可在CNS损伤后促进再生。
Myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs) contribute to failed regeneration after neuronal injury. MAIs and CSPGs stimulate intracellular signals including the activation of RhoA and Rho kinase to block axonal extension through targeted modifications to the cytoskeleton. RhoA and ROCK are promising targets for therapeutic intervention to promote CNS repair; however, their ubiquitous expression will limit the specificity of drugs targeted to these molecules. We have identified the cytosolic phosphoprotein CRMP4b (collapsin-response mediator protein 4b) as a protein that physically and functionally interacts with RhoA to mediate neurite outgrowth inhibition. Short interfering RNA- mediated knockdown of CRMP4 promotes neurite outgrowth on myelin substrates, indicating a critical role for CRMP4b neurite outgrowth inhibition. Disruption of CRMP4b-RhoA binding with a competitive inhibitor attenuates neurite outgrowth inhibition on myelin and aggrecan substrates. Stimulation of neuronal growth cones with Nogo leads to colocalization of CRMP4b and RhoA at discrete regions within the actin-rich central and peripheral domains of the growth cone, indicative of a potential function in cytoskeletal rearrangements during neurite outgrowth inhibition. Together, these data indicate that a RhoA-CRMP4b complex forms in response to inhibitory challenges in the growth cone environment and regulates cytoskeletal dynamics at distinct sites necessary for axon outgrowth inhibition. Competitive inhibition of CRMP4b-RhoA binding suggests a novel, highly specific therapeutic avenue for promoting regeneration after CNS injury.