Alk3/Bmpr1a receptor is required for development of the atrioventricular canal into valves and annulus fibrosus

Vinciane Gaussin, Gregory E. Morley, Luk Cox, An Zwijsen, Kendra M. Vance, Lorin Emile, Yimin Tian, Jing Liu, Chull Hong, Dina Myers, Simon J. Conway, Christophe Depre, Yuji Mishina, Richard R. Behringer, Mark C. Hanks, Michael D. Schneider, Danny Huylebroeck, Glenn I. Fishman, John B.E. Burch, Stephen F. Vatner

Research output: Contribution to journalArticle

107 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)219-226
Number of pages8
JournalCirculation research
Volume97
Issue number3
DOIs
StatePublished - Aug 5 2005

Keywords

  • Atrioventricular canal
  • Bone morphogenetic protein signaling
  • Cre-lox system
  • Heart development

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Gaussin, V., Morley, G. E., Cox, L., Zwijsen, A., Vance, K. M., Emile, L., Tian, Y., Liu, J., Hong, C., Myers, D., Conway, S. J., Depre, C., Mishina, Y., Behringer, R. R., Hanks, M. C., Schneider, M. D., Huylebroeck, D., Fishman, G. I., Burch, J. B. E., & Vatner, S. F. (2005). Alk3/Bmpr1a receptor is required for development of the atrioventricular canal into valves and annulus fibrosus. Circulation research, 97(3), 219-226. https://doi.org/10.1161/01.RES.0000177862.85474.63