The p53 Pathway Controls SOX2-Mediated Reprogramming in the Adult Mouse Spinal Cord

Abstract

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.