TAp73 Acts via the bHLH Hey2 to Promote Long-Term Maintenance of Neural Precursors

Increasing evidence suggests that deficits in adult stem cell maintenance cause aberrant tissue repair and premature aging [ 1]. While the mechanisms regulating stem cell longevity are largely unknown, recent studies have implicated p53 and its family member p63. Both proteins regulate organismal aging [ 2–4] as well as survival and self-renewal of tissue stem cells [ 5–9]. Intriguingly, haploinsufficiency for a third family member, p73, causes age-related neurodegeneration [ 10]. While this phenotype is at least partially due to loss of the ΔNp73 isoform, a potent neuronal prosurvival protein [ 11–16], a recent study showed that mice lacking the other p73 isoform, TAp73, have perturbations in the hippocampal dentate gyrus [ 17], a major neurogenic site in the adult brain. These findings, and the link between the p53 family, stem cells, and aging, suggest that TAp73 might play a previously unanticipated role in maintenance of neural stem cells. Here, we have tested this hypothesis and show that TAp73 ensures normal adult neurogenesis by promoting the long-term maintenance of neural stem cells. Moreover, we show that TAp73 does this by transcriptionally regulating the bHLH Hey2, which itself promotes neural precursor maintenance by preventing premature differentiation. ► TAp73, a p53 family member, promotes long-term maintenance of neural stem cells ► TAp73 loss causes depletion of neural precursors and decreased adult neurogenesis ► TAp73 promotes stem cell maintenance by transcriptionally regulating the bHLH Hey2 ► Hey2 itself promotes neural stem cell maintenance by preventing differentiation