Cell Biology, Hospital for Sick Children, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
Curr Biol. 2010 Nov 23;20(22):2058-65. doi: 10.1016/j.cub.2010.10.029. Epub 2010 Nov 11.
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.
越来越多的证据表明，成体干细胞维持能力的缺陷导致异常的组织修复和过早衰老[1]。尽管调节干细胞寿命的机制在很大程度上尚不清楚，但最近的研究已经涉及到 p53 及其家族成员 p63。这两种蛋白质都调节着生物体的衰老[2-4]以及组织干细胞的存活和自我更新[5-9]。有趣的是，第三个家族成员 p73 的单倍不足会导致与年龄相关的神经退行性变[10]。虽然这种表型至少部分是由于ΔNp73 同工型的缺失，这是一种有效的神经元存活蛋白[11-16]，但最近的一项研究表明，缺乏另一种 p73 同工型 TAp73 的小鼠在海马齿状回[17]中出现紊乱，海马齿状回是成年大脑中的主要神经发生部位。这些发现，以及 p53 家族、干细胞和衰老之间的联系，表明 TAp73 可能在维持神经干细胞方面发挥了以前未预料到的作用。在这里，我们检验了这一假设，并表明 TAp73 通过促进神经干细胞的长期维持来确保正常的成年神经发生。此外，我们还表明，TAp73 通过转录调节 bHLH Hey2 来实现这一点，Hey2 通过防止过早分化来促进神经前体细胞的维持。
