Division of Life Science, State Key Laboratory of Molecular Neuroscience; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou, 510006, China.
eNeuro. 2017 Jan 13;3(6). doi: 10.1523/ENEURO.0358-16.2016. eCollection 2016 Nov-Dec.
Neuronal mammalian target of rapamycin (mTOR) activity is a critical determinant of the intrinsic regenerative ability of mature neurons in the adult central nervous system (CNS). However, whether its action also applies to peripheral nervous system (PNS) neurons after injury remains elusive. To address this issue unambiguously, we used genetic approaches to determine the role of mTOR signaling in sensory axon regeneration in mice. We showed that deleting mTOR in dorsal root ganglion (DRG) neurons suppressed the axon regeneration induced by conditioning lesions. To establish whether the impact of mTOR on axon regeneration results from functions of mTOR complex 1 (mTORC1) or 2 (mTORC2), two distinct kinase complexes, we ablated either Raptor or Rictor in DRG neurons. We found that suppressing mTORC1 signaling dramatically decreased the conditioning lesion effect. In addition, an injury to the peripheral branch boosts mTOR activity in DRG neurons that cannot be completely inhibited by rapamycin, a widely used mTOR-specific inhibitor. Unexpectedly, examining several conditioning lesion-induced pro-regenerative pathways revealed that Raptor deletion but not rapamycin suppressed Stat3 activity in neurons. Therefore, our results demonstrate that crosstalk between mTOR and Stat3 signaling mediates the conditioning lesion effect and provide genetic evidence that rapamycin-resistant mTOR activity contributes to the intrinsic axon growth capacity in adult sensory neurons after injury.
哺乳动物雷帕霉素靶蛋白（mTOR）在成熟神经元的内在再生能力方面起着关键作用，这是成年中枢神经系统（CNS）的一个关键决定因素。然而，其在损伤后对周围神经系统（PNS）神经元的作用仍然难以捉摸。为了明确解决这个问题，我们使用遗传方法来确定 mTOR 信号在小鼠感觉轴突再生中的作用。我们发现，在背根神经节（DRG）神经元中删除 mTOR 会抑制条件性损伤诱导的轴突再生。为了确定 mTOR 对轴突再生的影响是否来自 mTOR 复合物 1（mTORC1）或 2（mTORC2）的功能，我们在 DRG 神经元中缺失了 Raptor 或 Rictor。我们发现，抑制 mTORC1 信号显著降低了条件性损伤的效果。此外，外周分支的损伤会增加 DRG 神经元中的 mTOR 活性，但这种活性不能被雷帕霉素（一种广泛使用的 mTOR 特异性抑制剂）完全抑制。出乎意料的是，研究几种条件性损伤诱导的促再生途径发现，Raptor 的缺失而非雷帕霉素抑制了神经元中的 Stat3 活性。因此，我们的结果表明，mTOR 和 Stat3 信号之间的串扰介导了条件性损伤的效果，并提供了遗传证据表明，损伤后成年感觉神经元中雷帕霉素抗性 mTOR 活性有助于内在轴突生长能力。
