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J Biol Chem. 2014 Jul 4;289(27):18681-92. doi: 10.1074/jbc.M114.554584. Epub 2014 May 15.

Yap1 is required for endothelial to mesenchymal transition of the atrioventricular cushion.

Author information

1
From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
2
the Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts 02115, the Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, 30669 Hannover, Germany.
3
the Department of Developmental and Regenerative Biology, Center for Molecular Cardiology of the Child Health and Development Institute, the Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York 10029.
4
the Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, and.
5
From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China, zhoubin@sibs.ac.cn.

Abstract

Cardiac malformations due to aberrant development of the atrioventricular (AV) valves are among the most common forms of congenital heart diseases. Normally, heart valve mesenchyme is formed from an endothelial to mesenchymal transition (EMT) of endothelial cells of the endocardial cushions. Yes-associated protein 1 (YAP1) has been reported to regulate EMT in vitro, in addition to its known role as a major regulator of organ size and cell proliferation in vertebrates, leading us to hypothesize that YAP1 is required for heart valve development. We tested this hypothesis by conditional inactivation of YAP1 in endothelial cells and their derivatives. This resulted in markedly hypocellular endocardial cushions due to impaired formation of heart valve mesenchyme by EMT and to reduced endocardial cell proliferation. In endothelial cells, TGFβ induces nuclear localization of Smad2/3/4 complex, which activates expression of Snail, Twist1, and Slug, key transcription factors required for EMT. YAP1 interacts with this complex, and loss of YAP1 disrupts TGFβ-induced up-regulation of Snail, Twist1, and Slug. Together, our results identify a role of YAP1 in regulating EMT through modulation of TGFβ-Smad signaling and through proliferative activity during cardiac cushion development.

KEYWORDS:

Cardiac Development; Development; Epithelial-Mesenchymal Transition (EMT); Heart; Heart Development

PMID:
24831012
PMCID:
PMC4081914
DOI:
10.1074/jbc.M114.554584
[Indexed for MEDLINE]
Free PMC Article

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