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SUMMARY Although the adult mammalian spinal cord lacks intrinsic neurogenic capacity, glial cells can be reprogrammed in vivo to generate neurons after spinal cord injury (SCI). How this reprogramming process is molecularly regulated, however, is not clear. Through a series of in vivo screens, we show here that the p53-dependent pathway constitutes a critical checkpoint for SOX2-mediated reprogramming of resident glial cells in the adult mouse spinal cord. While it has no effect on the reprogramming efficiency, the p53 pathway promotes cell cycle exit of SOX2-induced adult neuroblasts (iANBs). As such, silencing of either p53 or p21 markedly boosts the overall production of iANBs. A neurotrophic milieu supported by BDNF and NOG can robustly enhance maturation of these iANBs into diverse but predominantly glutamatergic neurons. Together, these findings have uncovered critical molecular and cellular checkpoints that may be manipulated to boost neuron regeneration after SCI.

The SCAN domain is described as a highly conserved, leucine-rich motif of approximately 60 amino acids found at the amino-terminal end of zinc finger transcription factors. Although no specific biological function has been attributed to the SCAN domain, its predicted amphipathic secondary structure led to the suggestion that this domain may mediate protein-protein associations. The SCAN or leucine-rich domain, originally identified by its homology with similar elements in several zinc finger transcription factors, consists of approximately 60 amino acids and is rich in leucine and glutamic acid residues (1). Most SCAN domain sequences are linked to Cys 2 -His 2 zinc finger motifs through their carboxyl-terminal end. Although the function of the SCAN domain has not yet been elucidated, the predicted amphipathic structure of the domain led to the suggestion that SCAN box elements have the capacity to interact with other proteins, in particular with components of the transcriptional machinery (1).The zinc finger protein ZNF202 1 is expressed in two common splice variants, here referred to as m1 and m3 (2). Whereas the m1-splice form encodes a full-length protein of 648 amino acids with a SCAN box, a KRAB repression domain, and eight Cys 2 -His 2 zinc finger motifs, the 133 amino acid product of the m3-splice form encompasses only the SCAN domain.2 These splice forms are conserved in the murine ZNF202 homolog, suggesting that the SCAN motif itself is an independent functional domain.3

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.