Astrocyte-Specific Deletion of Sox2 Promotes Functional Recovery After Traumatic Brain Injury

Abstract

Injury to the adult brain induces activation of local astrocytes, which serves as a compensatory response that modulates tissue damage and recovery. However, the mechanism governing astrocyte activation during brain injury remains largely unknown. Here we provide in vivo evidence 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 chromatin immunoprecipitation-seq analysis of mouse cortical tissues reveals that SOX2 binds to regulatory regions of genes associated with signaling pathways that control glial cell activation, such as Nr2e1, Mmd2, Wnt7a, and Akt2. Astrocyte-specific deletion of Sox2 in adult mice greatly diminishes glial response to controlled cortical impact injury and, most unexpectedly, dampens injury-induced cortical loss and benefits behavioral recovery of mice after injury. Together, these results uncover an essential role of SOX2 in somatic cells under pathological conditions and indicate that SOX2-dependent astrocyte activation could be targeted for functional recovery after traumatic brain injury.

The stem cell transcription factor SOX2 is essential for astrocyte maturation and controls animal hyperactive behavior

“…Alternatively, the functional redundancy of between SOX2 and SOX1/3 (12) may be accountable for normal proliferation of Sox2-deficient astrocytes. In contrast, a recent study reported that SOX2 disruption in adult quiescent astrocytes inhibits their proliferation and activation in response to traumatic brain injury, which was assessed by BrdU labeling and GFAP expression (16). These data suggest that SOX2 regulation of astrocyte proliferation is context-dependent of CNS development vs injury.…”

“…To gain molecular insights into the role of SOX2 in postnatal astrocyte maturation and function, we sought to identify SOX2-regulated target genes. We analyzed the SOX2 ChIP-seq dataset which was previously deposited to the Gene Expression Omnibus (GEO) data repository (GSE85213) (16). The dataset consists of raw reads of one input and three biological replicates of SOX2-immunoprecipitated chromatin from the adult murine cerebral cortex, where SOX2 is highly enriched in astrocytes, and, to a much lower level, in oligodendrocyte progenitor cells (OPCs) yet absent from neurons, microglia, or vascular cells (13,14,16).…”

“…We analyzed the SOX2 ChIP-seq dataset which was previously deposited to the Gene Expression Omnibus (GEO) data repository (GSE85213) (16). The dataset consists of raw reads of one input and three biological replicates of SOX2-immunoprecipitated chromatin from the adult murine cerebral cortex, where SOX2 is highly enriched in astrocytes, and, to a much lower level, in oligodendrocyte progenitor cells (OPCs) yet absent from neurons, microglia, or vascular cells (13,14,16). After mapping and peak-calling, 9,602 SOX2-bound sites were identified with FDR < 0.05 (Table S1), 33.6% of which were located at the upstream regions of the nearest genes and 35.8% at intronic regions (Fig.…”

“…Astrocytes, the most abundant glial cells in the CNS, express high level of SOX2 in the developing and adult CNS (11,13,15,16). Whether astroglial SOX2-deficiency contributes to neural developmental defects and/or behavioral impairments remains elusive.…”

Concepts toward directing human astroplasticity to promote neuroregeneration

“…Sox2 is another similar candidate. Astrocyte‐specific deletion of Sox2 in adult mice greatly diminishes glial response to controlled cortical impact injury, dampens injury‐induced cortical loss, and benefits behavioral recovery of mice (Chen et al, ). Another important transcription regulator identified to modulate astrocyte maturation is NFIX.…”