Zhou Feng-Quan, Walzer Mark, Wu Yao-Hong, Zhou Jiang, Dedhar Shoukat, Snider William D
Neuroscience Center, 8109 Neuroscience Research Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
J Cell Sci. 2006 Jul 1;119(Pt 13):2787-96. doi: 10.1242/jcs.03016. Epub 2006 Jun 13.
Chondroitin sulfate proteoglycans (CSPGs) and myelin-based inhibitors are the most studied inhibitory molecules in the adult central nervous system. Unlike myelin-based inhibitors, few studies have reported ways to overcome the inhibitory effect of CSPGs. Here, by using regenerating adult dorsal root ganglion (DRG) neurons, we show that chondroitin sulfate proteoglycans inhibit axon assembly by a different mechanism from myelin-based inhibitors. Furthermore, we show that neither Rho inhibition nor cAMP elevation rescues extracellular factor-induced axon assembly inhibited by CSPGs. Instead, our data suggest that CSPGs block axon assembly by interfering with integrin signaling. Surprisingly, we find that nerve growth factor (NGF) promotes robust axon growth of regenerating DRG neurons over CSPGs. We have found that, unlike naive neurons that require simultaneous activation of neurotrophin and integrin pathways for axon assembly, either neurotrophin or integrin signaling alone is sufficient to induce axon assembly of regenerating neurons. Thus, our results suggest that the ability of NGF to overcome CSPG inhibition in regenerating neurons is probably due to the ability of regenerating neurons to assemble axons using an integrin-independent pathway. Finally, our data show that the GSK-3beta-APC pathway, previously shown to mediate developing axon growth, is also necessary for axon regeneration.
硫酸软骨素蛋白聚糖（CSPGs）和髓磷脂相关抑制因子是在成体中枢神经系统中研究最多的抑制性分子。与髓磷脂相关抑制因子不同，鲜有研究报道克服CSPGs抑制作用的方法。在此，通过使用成年再生背根神经节（DRG）神经元，我们发现硫酸软骨素蛋白聚糖通过一种与髓磷脂相关抑制因子不同的机制抑制轴突组装。此外，我们发现抑制Rho或提高cAMP水平均不能挽救由CSPGs抑制的细胞外因子诱导的轴突组装。相反，我们的数据表明CSPGs通过干扰整合素信号传导来阻断轴突组装。令人惊讶的是，我们发现神经生长因子（NGF）能促进再生DRG神经元在CSPGs存在的情况下强劲地长出轴突。我们发现，与幼稚神经元不同，幼稚神经元轴突组装需要神经营养因子和整合素途径同时激活，而再生神经元单独通过神经营养因子或整合素信号传导就足以诱导轴突组装。因此，我们的结果表明，NGF克服再生神经元中CSPG抑制的能力可能归因于再生神经元使用不依赖整合素的途径组装轴突的能力。最后，我们的数据表明，先前显示介导发育中轴突生长的GSK-3β-APC途径对轴突再生也是必需的。
