EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway
EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway
复制标题
DOI：
10.1038/nature14102
复制
发表时间：
2015-01-08
期刊：
影响因子：
64.8
通讯作者：
Hilliard, Massimo A.
中科院分区：
文献类型：
--
作者：
Neumann, Brent;Coakley, Sean;Hilliard, Massimo A.
神经系统损伤后的功能再生需要横断的轴突与其原始的靶组织重新连接。轴突融合是几个物种中发现的一种自发的再生机制，它提供了一种实现靶重新连接的有效手段，因为再生的轴突能够与自己分离的轴突片段接触并融合，从而重建原始轴突束(1-7)。在这里，我们报道了秀丽隐杆线虫这一过程的分子特征，揭示了EFF-1 FusoGen在轴突切断后亚细胞定位的动态变化，并确立了磷脂酰丝氨酸(PS)和PS受体(PSR-1)是轴突融合的关键成分。PSR-1在再生神经元中发挥细胞自主功能，而不是在其典型的信号通路(8)中发挥作用，而是在平行的吞噬途径中发挥作用，其中包括转甲状腺激素蛋白TTR-52以及CED-7、NRF-5和CED-6(参考文献9-12)。我们发现TTR-52与暴露在损伤轴突上的PS结合，并能在损伤后几小时恢复融合。我们认为PS作为远端片段的“拯救我”信号，允许保守的细胞凋亡清除分子在神经系统再生过程中重建轴突的完整性。
Functional regeneration after nervous system injury requires transected axons to reconnect with their original target tissue. Axonal fusion, a spontaneous regenerative mechanism identified in several species, provides an efficient means of achieving target reconnection as a regrowing axon is able to contact and fuse with its own separated axon fragment, thereby re-establishing the original axonal tract(1-7). Here we report a molecular characterization of this process in Caenorhabditis elegans, revealing dynamic changes in the subcellular localization of the EFF-1 fusogen after axotomy, and establishing phosphatidylserine (PS) and the PS receptor (PSR-1) as critical components for axonal fusion. PSR-1 functions cell-autonomously in the regrowing neuron and, instead of acting in its canonical signalling pathway(8), acts in a parallel phagocytic pathway that includes the transthyretin protein TTR-52, as well as CED-7, NRF-5 and CED-6 (refs 9-12). We show that TTR-52 binds to PS exposed on the injured axon, and can restore fusion several hours after injury. We propose that PS functions as a 'save-me' signal for the distal fragment, allowing conserved apoptotic cell clearance molecules to function in reestablishing axonal integrity during regeneration of the nervous system.