Hollis Edmund R, Jamshidi Pouya, Löw Karin, Blesch Armin, Tuszynski Mark H
Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093-0626, USA.
Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7215-20. doi: 10.1073/pnas.0810624106. Epub 2009 Apr 9.
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.
对中枢神经系统环境进行的几种实验性操作成功诱导了感觉轴突和延髓脊髓运动轴突的再生，但未能诱导皮质脊髓轴突的再生，这表明细胞内在机制限制了这类关键运动神经元的再生。我们假设增强内在神经元生长机制将促进成年皮质脊髓运动轴突的再生。慢病毒载体用于在V层皮质脊髓运动神经元中过表达脑源性神经营养因子（BDNF）受体trkB。在皮质下轴突切断术后，trkB转导诱导皮质脊髓轴突向表达BDNF的皮质下损伤部位再生。在没有trkB过表达的情况下，未发生再生。通过Shc/FRS-2激活域突变选择性删除经典的、trkB介导的神经突生长信号，可阻止细胞外信号调节激酶（Erk）激活并消除再生。这些发现支持了以下假设：成年皮质脊髓轴突的难治性再生状态至少部分可归因于神经元内在机制，并且Erk信号的激活可引发皮质脊髓束再生。
