Abstract

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 Delta Np73 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