Wolchinsky Zohar, Shivtiel Shoham, Kouwenhoven Evelyn Nathalie, Putin Daria, Sprecher Eli, Zhou Huiqing, Rouleau Matthieu, Aberdam Daniel
INSERTECH, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centrum, The Netherlands.
Stem Cell Res. 2014 Jan;12(1):49-59. doi: 10.1016/j.scr.2013.09.015. Epub 2013 Oct 6.
The transcription factor p63, member of the p53 gene family, encodes for two main isoforms, TAp63 and ΔNp63 with distinct functions on epithelial homeostasis and cancer. Recently, we discovered that TAp63 is essential for in vitro cardiogenesis and heart development in vivo. TAp63 is expressed by embryonic endoderm and acts on cardiac progenitors by a cell-non-autonomous manner. In the present study, we search for cardiogenic secreted factors that could be regulated by TAp63 and, by ChIP-seq analysis, identified Angiomodulin (AGM), also named IGFBP7 or IGFBP-rP1. We demonstrate that AGM is necessary for cardiac commitment of embryonic stem cells (ESCs) and its regulation depends on TAp63 isoform. TAp63 directly activates both AGM and Activin-A during ESC cardiogenesis while these secreted factors modulate TAp63 gene expression by a feedback loop mechanism. The molecular circuitry controlled by TAp63 on AGM/Activin-A signaling pathway and thus on cardiogenesis emphasizes the importance of p63 during early cardiac development.
转录因子p63是p53基因家族的成员，编码两种主要的异构体TAp63和ΔNp63，它们在上皮细胞稳态和癌症方面具有不同的功能。最近，我们发现TAp63对于体外心脏发生和体内心脏发育至关重要。TAp63由胚胎内胚层表达，并以非细胞自主方式作用于心脏祖细胞。在本研究中，我们寻找可能受TAp63调控的心脏发生分泌因子，并通过ChIP-seq分析鉴定出血管调节蛋白（AGM），也称为胰岛素样生长因子结合蛋白7（IGFBP7）或胰岛素样生长因子结合蛋白相关蛋白1（IGFBP-rP1）。我们证明AGM对于胚胎干细胞（ESC）的心脏定向分化是必需的，其调控依赖于TAp63异构体。在ESC心脏发生过程中，TAp63直接激活AGM和激活素A，而这些分泌因子通过反馈环机制调节TAp63基因表达。TAp63在AGM/激活素A信号通路以及心脏发生上所控制的分子回路，强调了p63在早期心脏发育过程中的重要性。
