Astrocyte-specific deletion of SOX2 promotes recovery after traumatic brain injury

Injury to the adult brain induces activation of resident astrocytes, which serves as a compensatory response modulating tissue damage and recovery. However, the mechanism governing astrocyte activation and the role of reactive astrocytes remain largely unknown. Here we show that SOX2, a transcription factor critical for stem cells and brain development, is also required for injury-induced activation of adult cortical astrocytes. Genome-wide ChIP-seq analysis reveals that SOX2 binds to regulatory regions of genes associated with signaling pathways controlling reactive gliosis, such as Socs3, Nr2e1, Notch1, and Akt2. Inducible deletion of Sox2 in adult astrocytes greatly diminishes their response to traumatic injury and, most unexpectedly, restricts injury-induced cortical loss. Together, these results uncover an essential role of SOX2 in terminally differentiated cells and implicate that SOX2-dependent reactive astrocytes may be targeted for regeneration after traumatic brain injury. Overall design: SOX2 (1 input dataset, 3 immunoprecipitation datasets)

成年大脑损伤可激活常驻星形胶质细胞（resident astrocytes），这是一类调控组织损伤与修复的代偿性反应。然而，调控星形胶质细胞激活的分子机制，以及反应性星形胶质细胞（reactive astrocytes）的功能，目前仍未完全阐明。本研究发现，SOX2——一种对干细胞及脑发育至关重要的转录因子——同样是成年皮层星形胶质细胞损伤诱导激活所必需的。全基因组染色质免疫共沉淀测序（ChIP-seq）分析显示，SOX2可结合与反应性胶质增生（reactive gliosis）相关信号通路基因的调控区域，例如Socs3、Nr2e1、Notch1及Akt2。在成年星形胶质细胞中诱导性敲除Sox2，可大幅削弱其对创伤性损伤的应答，且最出乎意料的是，还能抑制损伤诱导的皮层组织丢失。综上，本研究揭示了SOX2在终末分化细胞中的核心功能，并提示依赖SOX2的反应性星形胶质细胞可作为创伤性脑损伤后再生治疗的潜在靶点。实验整体设计：SOX2（1份输入数据集，3份免疫沉淀数据集）