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

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 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.

ISDN2014_0058: p63 and p73 coordinate p53 function to determine the balance between survival, cell death and senescence in adult neural precursor cells

“…p63 þ / À and p73 þ / À mice both had significantly fewer adult-born neurons than wild-type mice, and p63 þ / À ;p73 þ / À mice had less than 50% of wild-type levels ( Figure 1j). Thus, p63 and p73 are individually important for adult hippocampal neurogenesis, as previously reported, 4,10,[12][13][14] and haploinsufficiency for both causes greater deficits than haploinsufficiency for either gene alone.…”

“…The DNp63 and TAp73 isoforms are necessary for NPC survival, self-renewal, and long-term maintenance in the murine brain. 4,10,[12][13][14] To ask about potential interactions between these two family members, we crossed p63 þ / À 15 and p73 þ / À 16 mice and characterized hippocampal NPCs and neurogenesis in 3-month-old p63 þ / þ ; p73 þ / À , p63 þ / À ;p73 þ / þ , and p63 þ / À ; p73 þ / À mice. Morphological analysis showed that the hippocampus was grossly similar to wild-type mice in the heterozygous genotypes (Figure 1a).…”

“…10,11 We therefore asked whether this enhanced senescence was also seen in TAp73 À / À mice by staining the dentate gyrus for SA-b-gal. This analysis showed that, although the dentate gyrus is truncated in TAp73 mice, 10,11 the total number of SA-b-gal-positive cells per dentate gyrus was almost doubled (Figure 6e).…”

“…In NPCs, the three predominantly expressed p53 family members are p53, DNp63, and TAp73. 4,[8][9][10][11][12][13][14] p53 regulates apoptosis and proliferation of NPCs, 8,9 DNp63 promotes survival by antagonizing p53-mediated activation of target genes such as p53-upregulated modulator of apoptosis (PUMA), 4 and TAp73 promotes selfrenewal 10,12-14 by transcriptionally regulating the Hey2 gene.10 Given these diverse activities, we asked whether these family members coordinately regulate NPC biology, using mice in which one or two copies of p53, p63, or p73 genes are deleted. We show that p63 and p73 interact to regulate p53-dependent NPC apoptosis versus senescence, thereby determining appropriate adult neurogenesis.…”

p73 Regulates Primary Cortical Neuron Metabolism: a Global Metabolic Profile

“…Clearly, since p73 is a transcription factor, the phenotype observed in p73-/-mice is in part linked to regulation of gene expression. Indeed, several genes that are involved in neuronal biology, such as, SOX-2 [27], Hey-2 [28], TRIM32 [29] and p75NTR [30], are either directly or indirectly regulated by TAp73 [31][32][33][34][35]. In addition, TAp73 controls the expression of miR-34a, suggesting that microRNAs [36,26] also participate in the multifunctional role of p73 in neurons, such as differentiation [26].…”