Hisamoto Naoki, Nagamori Yuki, Shimizu Tatsuhiro, Pastuhov Strahil I, Matsumoto Kunihiro
Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya, Japan.
PLoS Genet. 2016 Dec 16;12(12):e1006475. doi: 10.1371/journal.pgen.1006475. eCollection 2016 Dec.
The ability of specific neurons to regenerate their axons after injury is governed by cell-intrinsic regeneration pathways. However, the signaling pathways that orchestrate axon regeneration are not well understood. In Caenorhabditis elegans, initiation of axon regeneration is positively regulated by SVH-2 Met-like growth factor receptor tyrosine kinase (RTK) signaling through the JNK MAPK pathway. Here we show that SVH-4/DDR-2, an RTK containing a discoidin domain that is activated by collagen, and EMB-9 collagen type IV regulate the regeneration of neurons following axon injury. The scaffold protein SHC-1 interacts with both DDR-2 and SVH-2. Furthermore, we demonstrate that overexpression of svh-2 and shc-1 suppresses the delay in axon regeneration observed in ddr-2 mutants, suggesting that DDR-2 functions upstream of SVH-2 and SHC-1. These results suggest that DDR-2 modulates the SVH-2-JNK pathway via SHC-1. We thus identify two different RTK signaling networks that play coordinated roles in the regulation of axonal regeneration.
特定神经元在损伤后再生轴突的能力受细胞内在再生途径的调控。然而，协调轴突再生的信号通路尚未完全明确。在秀丽隐杆线虫中，轴突再生的起始受SVH - 2（一种类Met生长因子受体酪氨酸激酶（RTK））通过JNK MAPK途径的正向调控。在此，我们表明SVH - 4/DDR - 2（一种含有盘状结构域且被胶原蛋白激活的RTK）和IV型胶原蛋白EMB - 9可调节轴突损伤后神经元的再生。支架蛋白SHC - 1与DDR - 2和SVH - 2均相互作用。此外，我们证明svh - 2和shc - 1的过表达可抑制ddr - 2突变体中观察到的轴突再生延迟，这表明DDR - 2在SVH - 2和SHC - 1的上游发挥作用。这些结果表明DDR - 2通过SHC - 1调节SVH - 2 - JNK途径。因此，我们鉴定出两个在轴突再生调控中发挥协同作用的不同RTK信号网络。
