INSERM U898, Nice, France.
Stem Cells. 2011 Nov;29(11):1672-83. doi: 10.1002/stem.723.
p63, a member of the p53 family, is essential for skin morphogenesis and epithelial stem cell maintenance. Here, we report an unexpected role of TAp63 in cardiogenesis. p63 null mice exhibit severe defects in embryonic cardiac development, including dilation of both ventricles, a defect in trabeculation and abnormal septation. This was accompanied by myofibrillar disarray, mitochondrial disorganization, and reduction in spontaneous calcium spikes. By the use of embryonic stem cells (ESCs), we show that TAp63 deficiency prevents expression of pivotal cardiac genes and production of cardiomyocytes. TAp63 is expressed by endodermal cells. Coculture of p63-knockdown ESCs with wild-type ESCs, supplementation with Activin A, or overexpression of GATA-6 rescue cardiogenesis. Therefore, TAp63 acts in a non-cell-autonomous manner by modulating expression of endodermal factors. Our findings uncover a critical role for p63 in cardiogenesis that could be related to human heart disease.
p63 是 p53 家族的一员，对于皮肤形态发生和上皮干细胞维持至关重要。在这里，我们报告了 TAp63 在心脏发生中的一个意外作用。p63 缺失小鼠表现出胚胎心脏发育的严重缺陷，包括两个心室扩张、小梁形成缺陷和异常间隔。这伴随着肌原纤维排列紊乱、线粒体组织紊乱和自发钙峰减少。通过使用胚胎干细胞（ESCs），我们表明 TAp63 缺乏会阻止关键心脏基因的表达和心肌细胞的产生。TAp63 由内胚层细胞表达。与野生型 ESCs 共培养的 p63 敲低 ESCs、添加 Activin A 或过表达 GATA-6 可挽救心脏发生。因此，TAp63 通过调节内胚层因子的表达以非细胞自主的方式发挥作用。我们的发现揭示了 p63 在心脏发生中的关键作用，这可能与人类心脏病有关。
