Nociceptor Deletion of Tsc2 Enhances Axon Regeneration by Inducing a Conditioning Injury Response in Dorsal Root Ganglia
Nociceptor Deletion of Tsc2 Enhances Axon Regeneration by Inducing a Conditioning Injury Response in Dorsal Root Ganglia
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DOI：
10.1523/eneuro.0168-19.2019
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发表时间：
2019-05-01
期刊：
影响因子：
3.4
通讯作者：
Cavalli, Valeria
中科院分区：
文献类型：
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作者：
Carlin, Dan;Halevi, Alexandra E.;Cavalli, Valeria
PNS的神经元能够再生受损的轴突，这一过程需要大量的细胞资源来建立和维持远距离生长。mTORC1是一种有效的细胞代谢和蛋白质翻译调节剂，其基因激活可通过尚未确定的机制改善周围神经元的轴突再生。为了深入了解这一过程，我们通过基因缺失负调节因子Tsc2来激活小鼠伤害感受器中的mTORC1信号。围产期痛觉感受器中Tsc2的缺失增强了坐骨神经挤压后初始轴突的生长，但损伤后3 d轴突伸长率与对照组相似。在神经损伤前抑制mTORC1是抑制轴突生长增强的必要条件。纯化伤害感受器的基因表达分析显示，在没有损伤的情况下，缺乏tsc2的伤害感受器具有更高的再生相关转录因子（ratf）活性，包括cJun和Atf3。此外，损伤感受器Tsc2的缺失激活了背根神经节（DRG）的卫星胶质细胞和巨噬细胞，其方式与神经损伤相似。令人惊讶的是，在分离培养中，这些变化改善了轴突长度，但没有改善起始轴突的百分比。在成年小鼠中，aav8介导的Tsc2缺失再现了幼稚DRG的促再生环境，这表明这种表型不是由发育影响引起的。一致地，aav8介导的Tsc2缺失并没有改善坐骨神经挤压损伤后的行为恢复，尽管最初增强了轴突的生长。综上所述，这些数据表明，神经元mTORC1激活在DRG中诱导了一个不完全的促再生环境，促进了神经损伤后最初的轴突生长，而不是随后的轴突生长。
Neurons of the PNS are able to regenerate injured axons, a process requiring significant cellular resources to establish and maintain long-distance growth. Genetic activation of mTORC1, a potent regulator of cellular metabolism and protein translation, improves axon regeneration of peripheral neurons by an unresolved mechanism. To gain insight into this process, we activated mTORC1 signaling in mouse nociceptors via genetic deletion of its negative regulator Tsc2. Perinatal deletion of Tsc2 in nociceptors enhanced initial axon growth after sciatic nerve crush, however by 3 d post-injury axon elongation rate became similar to controls. mTORC1 inhibition prior to nerve injury was required to suppress the enhanced axon growth. Gene expression analysis in purified nociceptors revealed that Tsc2-deficient nociceptors had increased activity of regeneration-associated transcription factors (RATFs), including cJun and Atf3, in the absence of injury. Additionally, nociceptor deletion of Tsc2 activated satellite glial cells and macrophages in the dorsal root ganglia (DRG) in a similar manner to nerve injury. Surprisingly, these changes improved axon length but not percentage of initiating axons in dissociated cultures. The pro-regenerative environment in naive DRG was recapitulated by AAV8-mediated deletion of Tsc2 in adult mice, suggesting that this phenotype does not result from a developmental effect. Consistently, AAV8-mediated Tsc2 deletion did not improve behavioral recovery after a sciatic nerve crush injury despite initially enhanced axon growth. Together, these data show that neuronal mTORC1 activation induces an incomplete pro-regenerative environment in the DRG that improves initial but not later axon growth after nerve injury.