Published online before print July 21, 2005, doi: 10.1161/01.RES.0000177862.85474.63
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Submitted on February 22, 2005
Revised on July 5, 2005
Accepted on July 7, 2005
Alk3/Bmpr1a Receptor Is Required for Development of the Atrioventricular Canal Into Valves and Annulus Fibrosus
Vinciane Gaussin *;
From the Department of Cell Biology and Molecular Medicine (V.G., K.M.V., L.E., Y.T., J.L., C.H., C.D., S.F.V.), Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark; Leon H. Charney Division of Cardiology (G.E.M., D.M., G.I.F.), New York University School of Medicine, New York; Department of Developmental Biology (VIB7) (L.C., A.Z., D.H.), Flanders Interuniversity Institute for Biotechnology (VIB) and Laboratory of Molecular Biology, University of Leuven, Belgium; Cardiovascular Development Group (S.J.C.), Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis; National Institute of Environmental Health Sciences (Y.M.), Research Triangle Park, NC; University of Texas (R.R.B.), M.D. Anderson Cancer Center, Houston; Procter and Gamble Pharmaceuticals Health Care Research Center (M.C.H.), Mason Montgomery Road, Mason, Ohio; Departments of Medicine, Molecular and Cellular Biology, and Molecular Physiology and Biophysics (M.D.S.), Center for Cardiovascular Development, Baylor College of Medicine, Houston, Tex; Cell and Developmental Biology Program (J.B.E.B.), Fox Chase Cancer Center, Philadelphia, Penn.
* To whom correspondence should be addressed. E-mail: gaussivi{at}umdnj.edu.
Endocardial cushions are precursors of mature atrioventricular (AV) valves. Their formation is induced by signaling molecules originating from the AV myocardium, including bone morphogenetic proteins (BMPs). Here, we hypothesized that BMP signaling plays an important role in the AV myocardium during the maturation of AV valves from the cushions. To test our hypothesis, we used a unique Cre/lox system to target the deletion of a floxed Alk3 allele, the type IA receptor for BMPs, to cardiac myocytes of the AV canal (AVC). Lineage analysis indicated that cardiac myocytes of the AVC contributed to the tricuspid mural and posterior leaflets, the mitral septal leaflet, and the atrial border of the annulus fibrosus. When Alk3 was deleted in these cells, defects were seen in the same leaflets, ie, the tricuspid mural leaflet and mitral septal leaflet were longer, the tricuspid posterior leaflet was displaced and adherent to the ventricular wall, and the annulus fibrosus was disrupted resulting in ventricular preexcitation. The defects seen in mice with AVC-targeted deletion of Alk3 provide strong support for a role of Alk3 in human congenital heart diseases, such as Ebstein’s anomaly. In conclusion, our mouse model demonstrated critical roles for Alk3 signaling in the AV myocardium during the development of AV valves and the annulus fibrosus.
Key words: bone morphogenetic protein signaling • heart development • atrioventricular canal • Cre-lox system
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