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Induction of corticospinal regeneration by lentiviral trkB-induced Erk activation

机译:慢病毒trkB诱导的Erk激活诱导皮质脊髓的再生

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摘要

Several experimental manipulations of the CNS environment successfully elicit regeneration of sensory and bulbospinal motor axons but fail to elicit regeneration of corticospinal axons, suggesting that cell-intrinsic mechanisms limit the regeneration of this critical class of motor neurons. We hypothesized that enhancement of intrinsic neuronal growth mechanisms would enable adult corticospinal motor axon regeneration. Lentiviral vectors were used to overexpress the BDNF receptor trkB in layer V corticospinal motor neurons. After subcortical axotomy, trkB transduction induced corticospinal axon regeneration into subcortical lesion sites expressing BDNF. In the absence of trkB overexpression, no regeneration occurred. Selective deletion of canonical, trkB-mediated neurite outgrowth signaling by mutation of the Shc/FRS-2 activation domain prohibited Erk activation and eliminated regeneration. These findings support the hypothesis that the refractory regenerative state of adult corticospinal axons can be attributed at least in part to neuron-intrinsic mechanisms, and that activation of ERK signaling can elicit corticospinal tract regeneration.
机译:中枢神经系统环境的几个实验操作成功地引发了感觉和大脑脊髓运动轴突的再生,但未能引起皮质脊髓轴突的再生,这表明细胞内在机制限制了这一关键运动神经元类别的再生。我们假设内在神经元生长机制的增强将使成人皮质脊髓运动轴突再生。慢病毒载体用于在V层皮质脊髓运动神经元中过表达BDNF受体trkB。皮层下轴索切开术后,trkB转导诱导皮质脊髓轴突再生为表达BDNF的皮层下病变部位。在不存在trkB过表达的情况下,没有再生发生。 Shc / FRS-2激活域的突变选择性删除了典型的trkB介导的神经突增生信号,从而阻止Erk激活并消除了再生。这些发现支持这样的假说:成年皮质脊髓轴突的难治性再生状态至少可以部分归因于神经元内在机制,而ERK信号的激活可以引起皮质脊髓束的再生。

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