Epicardial retinoid X receptor α is required for myocardial growth and coronary artery formation

^*Institute of Molecular Medicine, University of California, San Diego, CA 92093; ^§Gene Expression Laboratory, The Salk Institute, La Jolla, CA 92186; ^∥Fox Chase Cancer Center, Philadelphia, PA 19111; ^**Cardiovascular Developmental Biology Center, Medical University of South Carolina, Charleston, SC 29425; ^††Department de Bioquimica i Biologia Molecular, Universitat de Barcelona, 08028 Barcelona, Spain; ^‡The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037; and ^‡‡Massachusetts General Hospital, MGH Cardiovascular Research Center CPZN 3208, 185 Cambridge Street, Boston, MA 02114-2790

Edited by Pierre Chambon, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch-Cedex, France, and approved November 3, 2005 (received for review May 26, 2005)

Abstract

Vitamin A signals play critical roles during embryonic development. In particular, heart morphogenesis depends on vitamin A signals mediated by the retinoid X receptor α (RXRα), as the systemic mutation of this receptor results in thinning of the myocardium and embryonic lethality. However, the molecular and cellular mechanisms controlled by RXRα signaling in this process are unclear, because a myocardium-restricted RXRα mutation does not perturb heart morphogenesis. Here, we analyze a series of tissue-restricted mutations of the RXRα gene in the cardiac neural crest, endothelial, and epicardial lineages, and we show that RXRα signaling in the epicardium is required for proper cardiac morphogenesis. Moreover, we detect an additional phenotype of defective coronary arteriogenesis associated with RXRα deficiency and identify a retinoid-dependent Wnt signaling pathway that cooperates in epicardial epithelial-to-mesenchymal transformation.

Footnotes

↵ §§ To whom correspondence may be addressed. E-mail: plozano{at}burnham.org or kchien{at}partners.org.
↵ † E.M. and M.Z. contributed equally to this work.
↵ ¶ Present address: Institució Catalana de Recerca i Estudis Avançats i Centre de Medicina Regenerativa de Barcelona, Dr. Aiguader 80, 08003 Barcelona, Spain.
Author contributions: P.R.-L. designed research; E.M., M.Z., A.R., Y.K., J.W., X.Z., S.W.K., and P.R.-L. performed research; J.B. and P.R.-L. contributed new reagents/analytic tools; E.M., M.Z., A.R., P.K., J.C.I.B., K.R.C., and P.R.-L. analyzed data; and P.R.-L. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: RXR, retinoid X receptor; EMT, epithelial-to-mesenchymal transformation; En, embryonic day n.