Neurotrophins support regenerative axon assembly over CSPGs by an ECM-integrin-independent mechanism
Neurotrophins support regenerative axon assembly over CSPGs by an ECM-integrin-independent mechanism
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DOI：
10.1242/jcs.03016
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发表时间：
2006-07-01
影响因子：
4
通讯作者：
Snider, William D.
中科院分区：
文献类型：
--
作者：
Zhou, Feng-Quan;Walzer, Mark;Snider, William D.
硫酸软骨素蛋白聚糖（CSPG）和髓鞘抑制剂是成人中枢神经系统中研究最多的抑制分子。与基于髓鞘的抑制剂不同，很少有研究报道克服CSPG抑制作用的方法。在这里，通过使用再生的成人背根神经节（DRG）神经元，我们表明硫酸软骨素蛋白聚糖抑制轴突组装从髓鞘为基础的抑制剂的不同机制。此外，我们表明，无论是Rho抑制，也不cAMP升高救援细胞外因子诱导的轴突组装抑制CSPGs。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）促进再生DRG神经元的轴突生长超过CSPGs。我们已经发现，与需要同时激活神经营养蛋白和整合素通路用于轴突组装的幼稚神经元不同，单独的神经营养蛋白或整合素信号传导足以诱导再生神经元的轴突组装。因此，我们的研究结果表明，在再生神经元中，NGF克服CSPG抑制的能力可能是由于再生神经元使用整合素非依赖性途径组装轴突的能力。最后，我们的数据表明，GSK-3 β-APC途径，以前显示介导发育轴突生长，也是轴突再生所必需的。
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-3 beta-APC pathway, previously shown to mediate developing axon growth, is also necessary for axon regeneration.