Zeb2 Is a Regulator of Astrogliosis and Functional Recovery after CNS Injury

The astrocytic response to injury is characterized on the cellular level, but our understanding of the molecular mechanisms controlling the cellular processes is incomplete. The astrocytic response to injury is similar to wound-healing responses in non-neural tissues that involve epithelial-to-mesenchymal transitions (EMTs) and upregulation in ZEB transcription factors. Here we show that injury-induced astrogliosis increases EMT-related genes expression, including Zeb2, and long non-coding RNAs, including Zeb2os, which facilitates ZEB2 protein translation. In mouse models of either contusive spinal cord injury or transient ischemic stroke, the conditional knockout of Zeb2 in astrocytes attenuates astrogliosis, generates larger lesions, and delays the recovery of motor function. These findings reveal ZEB2 as an important regulator of the astrocytic response to injury and suggest that astrogliosis is an EMT-like process, which provides a conceptual connection for the molecular and cellular similarities between astrogliosis and wound-healing responses in non-neural tissue. [Display omitted] •Zeb2 promotes astrogliosis and preservation of neurological function after injury•Naive astrocytes have Zeb2 mRNA, but protein expression is induced only after injury•Stroke and SCI also modify expression of several lncRNAs, including Zeb2os•Zeb2’s role and gene expression changes suggest astrogliosis is an EMT-like process Vivinetto et al. identify the EMT-related transcription factor ZEB2 as a regulator of the astrocytic response to injury. Mouse models of either stroke or SCI show that knockout of Zeb2 in astrocytes attenuates astrogliosis, increases lesion sizes, and delays recovery motor function. Altogether, the findings suggest that astrogliosis is an EMT-like process.