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TAp63 is important for cardiac differentiation of embryonic stem cells and heart development.

Author(s): Matthieu Rouleau, Alain Medawar, Laurent Hamon, Shoham Shivtiel, Zohar Wolchinsky, Huiqing Zhou, Laura De Rosa, Eleonora Candi, Stéphanie de la Forest Divonne, Marja L. Mikkola, Hans van Bokhoven, Caterina Missero, Gerry Melino, Michel Pucéat, Daniel Aberdam

Publication date: 2011-10-31

Journal: Stem Cells (Dayton, Ohio)

Keywords: Animals, Cell Differentiation, genetics, physiology, Cell Line, Embryonic Stem Cells, cytology, metabolism, ultrastructure, Flow Cytometry, Fluorescent Antibody Technique, GATA6 Transcription Factor, HMGB Proteins, Heart, embryology, growth & development, Immunoblotting, Mice, Mice, Knockout, Microscopy, Electron, Transmission, Phosphoproteins, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, SOXF Transcription Factors, Trans-Activators

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Abstract

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. Copyright © 2011 AlphaMed Press.