NT-3 promotes proprioceptive axon regeneration when combined with activation of the mTor intrinsic growth pathway but not with reduction of myelin extrinsic inhibitors.
NT-3 promotes proprioceptive axon regeneration when combined with activation of the mTor intrinsic growth pathway but not with reduction of myelin extrinsic inhibitors.
复制标题
NT-3与MTOR固有生长途径的激活结合使用时促进本体感受性轴突再生，而不是减少髓磷脂外部抑制剂。
DOI：
10.1016/j.expneurol.2016.05.021
复制
发表时间：
2016-09
影响因子：
5.3
通讯作者：
Smith GM
中科院分区：
文献类型：
--
作者：
Liu Y;Kelamangalath L;Kim H;Han SB;Tang X;Zhai J;Hong JW;Lin S;Son YJ;Smith GM
尽管先前的研究已经确定了几种刺激中枢神经系统轴突再生的策略，但广泛的再生和功能恢复仍然是主要的挑战，特别是对于大直径髓鞘轴突。在中枢神经系统内，髓磷脂被认为抑制轴突再生，而调节mTOR通路的活性促进受损轴突的再生。在这项研究中，我们在髓磷脂抑制蛋白三重敲除或DRG神经元中使用组成型活性（ca） Rheb激活mTOR后，通过背根进入区检测NT-3介导的感觉轴突再生，以确定环境抑制或内在生长途径激活的影响是否可以增强NT-3介导的再生。髓磷脂抑制蛋白的缺失显示感觉轴突再生的适度增强。在mTOR研究中，我们发现下游标记S6核糖体亚基的磷酸化决定了mTOR激活的显著年龄相关下降。体外培养的成人DRG神经元中caRheb的表达增加了S6磷酸化，并使神经突生长的总长度增加了一倍，而在雷帕霉素的存在下，这种情况被逆转。在成年雌性大鼠中，与单独表达NT-3相比，caRheb在DRG神经元和脊髓内NT-3中的联合表达使感觉轴突的再生增加了近3倍。使用网格跑道的本体感觉评估表明大直径髓鞘感觉传入的功能显著再生。我们的研究结果表明，carheb诱导的mTOR激活的增加增强了神经营养因子-3诱导的大直径髓鞘轴突的再生。
Although previous studies have identified several strategies to stimulate regeneration of CNS axons, extensive regeneration and functional recovery have remained a major challenge, particularly for large diameter myelinated axons. Within the CNS, myelin is thought to inhibit axon regeneration, while modulating activity of the mTOR pathway promotes regeneration of injured axons. In this study, we examined NT-3 mediated regeneration of sensory axons through the dorsal root entry zone in a triple knockout of myelin inhibitory proteins or after activation of mTOR using a constitutively active (ca) Rheb in DRG neurons to determine the influence of environmental inhibitory or activation of intrinsic growth pathways could enhance NT-3-mediate regeneration. Loss of myelin inhibitory proteins showed modest enhancement of sensory axon regeneration. In mTOR studies, we found a dramatic age related decrease in the mTOR activation as determined by phosphorylation of the downstream marker S6 ribosomal subunit. Expression of caRheb within adult DRG neurons in vitro increased S6 phosphorylation and doubled the overall length of neurite outgrowth, which was reversed in the presence of rapamycin. In adult female rats, combined expression of caRheb in DRG neurons and NT-3 within the spinal cord increased regeneration of sensory axons almost 3 fold when compared to NT-3 alone. Proprioceptive assessment using a grid runway indicates functionally significant regeneration of large-diameter myelinated sensory afferents. Our results indicate that caRheb-induced increase in mTOR activation enhances neurotrophin-3 induced regeneration of large-diameter myelinated axons.