Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Jiangsu Province, China.
State Key Laboratory of Neuroscience, Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
Glia. 2020 Jan;68(1):111-127. doi: 10.1002/glia.23707. Epub 2019 Aug 24.
Upon retina injury, Müller glia in the zebrafish retina respond by generating multipotent progenitors to repair the retina. However, the complete mechanisms underlying retina regeneration remain elusive. Here we report inflammation-induced mammalian target of rapamycin (mTOR) signaling in the Müller glia is essential for retina regeneration in adult zebrafish. We show after a stab injury, mTOR is rapidly activated in Müller glia and later Müller glia-derived progenitor cells (MGPCs). Importantly, mTOR is required for Müller glia dedifferentiation, as well as the proliferation of Müller glia and MGPCs. Interestingly, transient mTOR inhibition by rapamycin only reversibly suppresses MGPC proliferation, while its longer suppression by knocking down Raptor significantly inhibits the regeneration of retinal neurons. We further show mTOR promotes retina regeneration by regulating the mRNA expression of key reprogramming factors ascl1a and lin-28a, cell cycle-related genes and critical cytokines. Surprisingly, we identify microglia/macrophage-mediated inflammation as an important upstream regulator of mTOR in the Müller glia and it promotes retina regeneration through mTOR. Our study not only demonstrates the important functions of mTOR but also reveals an interesting link between inflammation and the mTOR signaling during retina regeneration.
在视网膜损伤后，斑马鱼视网膜中的 Müller 胶质细胞通过产生多能祖细胞来修复视网膜。然而，视网膜再生的完整机制仍不清楚。在这里，我们报告在成年斑马鱼中，炎症诱导的哺乳动物雷帕霉素靶蛋白（mTOR）信号在 Müller 胶质细胞中对于视网膜再生是必不可少的。我们发现，在刺伤损伤后，mTOR 在 Müller 胶质细胞中迅速被激活，随后在 Müller 胶质细胞衍生的祖细胞（MGPC）中被激活。重要的是，mTOR 对于 Müller 胶质细胞去分化以及 Müller 胶质细胞和 MGPC 的增殖都是必需的。有趣的是，雷帕霉素对 mTOR 的短暂抑制仅可逆地抑制 MGPC 的增殖，而通过敲低 Raptor 对其更长时间的抑制则显著抑制视网膜神经元的再生。我们进一步表明，mTOR 通过调节关键重编程因子 ascl1a 和 lin-28a、细胞周期相关基因和关键细胞因子的 mRNA 表达来促进视网膜再生。令人惊讶的是，我们发现小胶质细胞/巨噬细胞介导的炎症是 Müller 胶质细胞中 mTOR 的一个重要上游调节剂，它通过 mTOR 促进视网膜再生。我们的研究不仅证明了 mTOR 的重要功能，还揭示了炎症和 mTOR 信号在视网膜再生过程中的有趣联系。
