Collapsin Response Mediator Protein 4 Regulates Growth Cone Dynamics through the Actin and Microtubule Cytoskeleton
Collapsin Response Mediator Protein 4 Regulates Growth Cone Dynamics through the Actin and Microtubule Cytoskeleton
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DOI：
10.1074/jbc.m114.570440
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发表时间：
2014-10-24
影响因子：
4.8
通讯作者：
Fournier, Alyson E.
中科院分区：
文献类型：
--
作者：
Khazaei, Mohamad R.;Girouard, Marie-Pier;Fournier, Alyson E.
背景：生长锥细胞骨架的复杂调控控制着生长锥动力学。结果：CRMP4的缺失会破坏生长锥细胞骨架动力学、生长锥扩张和轴突生长。结论：CRMP4调控肌动蛋白和微管生长锥细胞骨架。意义：CRMP4在调节生长锥特性的细胞骨架动力学中起关键作用。生长锥细胞骨架的协调控制是轴突延伸和引导的基础。坍缩反应介质蛋白（CRMP）家族的成员调节微管和肌动蛋白细胞骨架，但它们在调节生长锥动力学中的作用在很大程度上仍未被探索。在这里，我们研究了CRMP4如何调节生长锥细胞骨架。CRMP4-/-小鼠海马神经元轴突延伸选择性减少，生长锥面积减少，而CRMP4的过表达增强了生长锥丝状足的形成和长度。从生物化学角度来看，CRMP4可以影响微管组装和f -肌动蛋白的体外捆绑。通过对CRMP4的结构功能分析，我们发现CRMP4对轴突生长和生长锥形态的影响依赖于微管组装，而丝状面延伸依赖于肌动蛋白捆绑。有趣的是，在来源于CRMP4-/-小鼠的神经元中，跟踪微管突出的EB3彗星的顺行运动显著减慢，而微管动力学的恢复需要CRMP4对肌动蛋白和微管细胞骨架的活性。总之，本研究确定了CRMP4在调节肌动蛋白和微管生长锥细胞骨架中的双重作用。
Background: Intricate regulation of the growth cone cytoskeleton controls growth cone dynamics. Results: Loss of CRMP4 disrupts growth cone cytoskeletal dynamics, growth cone expansion, and axon growth. Conclusion: CRMP4 regulates both the actin and microtubule growth cone cytoskeleton. Significance: CRMP4 plays a critical role in regulating cytoskeletal dynamics underlying growth cone properties.Coordinated control of the growth cone cytoskeleton underlies axon extension and guidance. Members of the collapsin response mediator protein (CRMP) family of cytosolic phosphoproteins regulate the microtubule and actin cytoskeleton, but their roles in regulating growth cone dynamics remain largely unexplored. Here, we examine how CRMP4 regulates the growth cone cytoskeleton. Hippocampal neurons from CRMP4-/- mice exhibited a selective decrease in axon extension and reduced growth cone area, whereas overexpression of CRMP4 enhanced the formation and length of growth cone filopodia. Biochemically, CRMP4 can impact both microtubule assembly and F-actin bundling in vitro. Through a structure function analysis of CRMP4, we found that the effects of CRMP4 on axon growth and growth cone morphology were dependent on microtubule assembly, whereas filopodial extension relied on actin bundling. Intriguingly, anterograde movement of EB3 comets, which track microtubule protrusion, slowed significantly in neurons derived from CRMP4-/- mice, and rescue of microtubule dynamics required CRMP4 activity toward both the actin and microtubule cytoskeleton. Together, this study identified a dual role for CRMP4 in regulating the actin and microtubule growth cone cytoskeleton.