Kinesin-1-powered microtubule sliding initiates axonal regeneration in Drosophila cultured neurons.
Kinesin-1-powered microtubule sliding initiates axonal regeneration in Drosophila cultured neurons.
复制标题
DOI：
10.1091/mbc.e14-10-1423
复制
发表时间：
2015-04-01
影响因子：
3.3
通讯作者：
Gelfand VI
中科院分区：
文献类型：
--
作者：
Lu W;Lakonishok M;Gelfand VI
微管滑动驱动果蝇神经元的初始轴突再生。轴突切断导致钙离子快速内流和随后的微管重组。Kinesin-1重链驱动反平行微管的滑动以推动轴突再生，而JNK途径通过促进微管滑动来促进轴突再生。了解轴突再生的机制对于开发创伤性脑和脊髓损伤的治疗方法具有重要的现实意义。在损伤部位发生了戏剧性的细胞骨架重组，微管参与了再生过程。在此之前，我们证明了在果蝇胚胎神经元中，微管通过传统的动蛋白(kinesin-1)滑动是启动轴突生长所必需的，并且当轴突生长完成时，滑动在发育过程中被下调。在这里，我们报告了在培养中机械切断果蝇神经元的轴突再生和再生长。再生神经元含有活跃的滑动微管；这种滑动，就像最初轴突生长时的滑动一样，是由Kinesin-1驱动的，是轴突再生所必需的。损伤导致细胞内钙离子迅速升高，损伤部位附近的微管解聚，随后形成局部混合极性的新微管阵列。这些事件是在再生的初始阶段重新激活微管滑动所必需的。此外，c-Jun氨基末端激酶通路通过促进受损成熟神经元中的微管滑动来促进再生。
Microtubule sliding drives initial axon regeneration in Drosophila neurons. Axotomy leads to fast calcium influx and subsequent microtubule reorganization. Kinesin-1 heavy chain drives the sliding of antiparallel microtubules to power axonal regrowth, and the JNK pathway promotes axonal regeneration by enhancing microtubule sliding. Understanding the mechanism underlying axon regeneration is of great practical importance for developing therapeutic treatment for traumatic brain and spinal cord injuries. Dramatic cytoskeleton reorganization occurs at the injury site, and microtubules have been implicated in the regeneration process. Previously we demonstrated that microtubule sliding by conventional kinesin (kinesin-1) is required for initiation of neurite outgrowth in Drosophila embryonic neurons and that sliding is developmentally down-regulated when neurite outgrowth is completed. Here we report that mechanical axotomy of Drosophila neurons in culture triggers axonal regeneration and regrowth. Regenerating neurons contain actively sliding microtubules; this sliding, like sliding during initial neurite outgrowth, is driven by kinesin-1 and is required for axonal regeneration. The injury induces a fast spike of calcium, depolymerization of microtubules near the injury site, and subsequent formation of local new microtubule arrays with mixed polarity. These events are required for reactivation of microtubule sliding at the initial stages of regeneration. Furthermore, the c-Jun N-terminal kinase pathway promotes regeneration by enhancing microtubule sliding in injured mature neurons.