AP-1cFos/JunB/miR-200a regulate the pro-regenerative glial cell response during axolotl spinal cord regeneration

Salamanders have the remarkable ability to functionally regenerate after spinal cord transection. In response to injury, GFAP+ glial cells in the axolotl spinal cord proliferate and migrate to replace the missing neural tube and create a permissive environment for axon regeneration. Molecular pathways that regulate the pro-regenerative axolotl glial cell response are poorly understood. Here we show axolotl glial cells up-regulate AP-1cFos/JunB after injury, which promotes a pro-regenerative glial cell response. Axolotl glial cells directly repress c-Jun expression via up-regulation of miR-200a. Inhibition of miR-200a during regeneration causes defects in axonal regrowth and transcriptomic analysis revealed that miR-200a inhibition leads to differential regulation of genes involved with reactive gliosis, the glial scar, ECM remodeling and axon guidance. This work identifies a novel role for miR-200a in inhibiting reactive gliosis in glial cell in axolotl during spinal cord regeneration

蝾螈（Salamanders）拥有脊髓横断后实现功能性再生的卓越能力。当遭遇损伤时，美西钝口螈（axolotl）脊髓内的胶质纤维酸性蛋白阳性（GFAP+）胶质细胞会发生增殖并迁移，以填补缺损的神经管，并为轴突再生构建允许性微环境。目前，调控促再生型美西钝口螈胶质细胞应答的分子通路尚不明晰。本研究证实，美西钝口螈的胶质细胞在损伤后会上调活化蛋白1（AP-1）的cFos/JunB复合体，进而促进促再生型胶质细胞应答。此外，美西钝口螈胶质细胞可通过上调微小RNA-200a（miR-200a）直接抑制c-Jun的表达。在再生过程中抑制miR-200a会导致轴突再生缺陷；转录组分析结果显示，抑制miR-200a会使与反应性胶质增生、胶质瘢痕、细胞外基质（ECM）重塑及轴突导向相关的基因出现差异表达。本研究明确了miR-200a在脊髓再生过程中，对美西钝口螈胶质细胞的反应性胶质增生发挥抑制作用的全新功能。