Netrin-1 and semaphorin 3A promote or inhibit cortical axon branching, respectively, by reorganization of the cytoskeleton
Netrin-1 and semaphorin 3A promote or inhibit cortical axon branching, respectively, by reorganization of the cytoskeleton
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DOI：
10.1523/jneurosci.4963-03.2004
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发表时间：
2004-03-24
影响因子：
5.3
通讯作者：
Kalil, K
中科院分区：
文献类型：
--
作者：
Dent, EW;Barnes, AM;Kalil, K
在许多中枢神经系统（CNS）通路中，靶标神经支配是通过轴突分支实现的，而非初级生长锥延伸至靶标。为了研究分支形成的机制，我们研究了吸引性和抑制性导向因子对皮质轴突分支的影响。我们发现，吸引皮质轴突的轴突导向因子Netrin - 1和碱性成纤维细胞生长因子 - 2（FGF - 2）使分支增加了50%以上，而排斥皮质轴突的信号素3A（Sema3A）则使分支抑制了50%。重要的是，这些因子均未对轴突长度产生显著影响。FGF - 2对分支的促进作用以及Sema3A对分支的抑制作用是通过对生长锥（扩张与塌陷）以及细胞骨架的相反作用介导的。FGF - 2在数小时内增加了生长锥中肌动蛋白的聚合以及微管环的形成，而Sema3A在数分钟内使肌动蛋白丝解聚，减弱了微管动力学，并使微管阵列塌陷。Netrin - 1促进轴突快速分支，通常不涉及生长锥。在局部应用Netrin - 1后30分钟内，轴突干上会从头形成分支，这会诱导丝状伪足中肌动蛋白丝的快速积聚。重要的是，肌动蛋白聚合增加和微管动力学增强是轴突分支发生所必需的。综上所述，这些结果表明，导向因子影响生长锥和轴突干处细胞骨架的组织和动力学，以促进或抑制轴突分支。与轴突生长无关，轴突对导向因子的分支反应可通过不同的细胞机制在不同的时间进程中发生。
In many CNS pathways, target innervation occurs by axon branching rather than extension of the primary growth cone into targets. To investigate mechanisms of branch formation, we studied the effects of attractive and inhibitory guidance cues on cortical axon branching. We found that netrin-1, which attracts cortical axons, and FGF-2 increased branching by >50%, whereas semaphorin 3A(Sema3A), which repels cortical axons, inhibited branching by 50%. Importantly, none of the factors affected axon length significantly. The increase in branching by FGF-2 and the inhibition of branching by Sema3A were mediated by opposing effects on the growth cone (expansion vs collapse) and on the cytoskeleton. FGF-2 increased actin polymerization and formation of microtubule loops in growth cones over many hours, whereas Sema3A depolymerized actin filaments, attenuated microtubule dynamics, and collapsed microtubule arrays within minutes. Netrin-1 promoted rapid axon branching, often without involving the growth cone. Branches formed de novo on the axon shaft within 30 min after local application of netrin-1, which induced rapid accumulation of actin filaments in filopodia. Importantly, increased actin polymerization and microtubule dynamics were necessary for axon branching to occur. Taken together, these results show that guidance factors influence the organization and dynamics of the cytoskeleton at the growth cone and the axon shaft to promote or inhibit axon branching. Independent of axon outgrowth, axon branching in response to guidance cues can occur over different time courses by different cellular mechanisms.