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The Role of Cell Autonomous Signaling by BMP in Endocardial Cushion Cells in AV Valvuloseptal Morphogenesis.


Etiology and Morphogenesis of Congenital Heart Disease: From Gene Function and Cellular Interaction to Morphology [Internet]. Tokyo: Springer; 2016. Chapter 22.
2016 Jun 25.

Author information

Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan
Cardiovascular Developmental Biology Center, Medical University of South Carolina Clemson University, Charleston, South Carolina, USA
Department of Pediatrics (Cardiology), Vanderbilt University, Nashville, Tennessee, USA
Pediatrics, Pharmacology and Toxicology, and Bioengineering, University of Louisville, Louisville, Kentucky, USA
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA
Pediatrics, Division of Pediatric Cardiology, Keio University School of Medicine, Tokyo, Japan
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC, 2925, USA
Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA
Pediatric Cardiology, Heart Institute, Tokyo Women’s Medical University, Tokyo, Japan
Department of Biological Materials Science, School of Dentistry, University of Michigan, Ann Arbor, MI, USA


Distal outgrowth and fusion of the mesenchymalized AV endocardial cushions are essential morphogenetic events in AV valvuloseptal morphogenesis. BMP-2 myocardial conditional knockout (cKO) mice die early by embryonic day (ED) 10.5 [1], hampering investigation of the role of BMP-2 in AV valvuloseptal morphogenesis after this stage. In our previous study, we localized BMP-2 and type I BMP receptors, BMPR1A and Alk2, in AV endocardial cushions [2, 3]. Based on their expression patterns, we hypothesize that autocrine signaling by BMP-2 within mesenchymalized AV cushions plays a critical role during AV valvuloseptal morphogenesis. To test this hypothesis, we employed recently generated endocardial/endocardial cushion-specific cre-driver line Nfact1Cre. Unlike a previously generated Nfatc1enCre line whose cre-mediated recombination is restricted to AV and OT endocardium, this Nfatc1Cre line confers cre-mediated recombination within the endocardial cells as well as their mesenchymal progeny. Using the Nfactc1Cre driver line, we disrupted BMPR1A (Alk3) and BMP-2 specifically from AV endocardium and endocardial cushions. BMPR1A endocardial cushion cKO (cKOEndo) mouse embryos died by ED 12.5 and exhibited failure of cellularization of AV cushions (Fig. 22.1a–c) and disruption of extracellular matrix (ECM) protein deposition in the cushion mesenchyme. On the other hand, AV cushion formation occurred in the BMP-2 cKOEndo mice that survived beyond the AV cushion formation stage because BMP-2 expression remained intact in the AV myocardium during AV cushion formation. BMP-2 cKOEndo mice exhibited perimembranous ventricular septal defects (VSDs) (Fig. 22.1d, e), defective deposition of ECMs in the membranous septum, and AV mitral valve dysplasia, suggesting the cell autonomous requirement of BMP-2 in AV endocardial cushions. BMP-2 cKOEndo did not exhibit muscular VSDs. These data strongly support our hypothesis that cell autonomous signaling by BMP-2 in the endocardial lineage plays a significant role in mesenchymalized AV cushions during AV valvuloseptal morphogenesis.

Copyright 2016, The Author(s).


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