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(Circulation Research. 1997;80:757-764.)
© 1997 American Heart Association, Inc.

Articles

Compartment-Selective Sensitivity of Cardiovascular Morphogenesis to Combinations of Retinoic Acid Receptor Gene Mutations

Robin Y. Lee, Jiangming Luo, Ronald M. Evans, Vincent Giguere, , Henry M. Sucov

From the Institute for Genetic Medicine (R.Y.L., H.M.S.), Department of Cell and Neurobiology, University of Southern California School of Medicine, Los Angeles; the Departments of Biochemistry, Medicine, and Oncology (J.L., V.G.), McGill University, and Molecular Oncology Group (J.L., V.G.), Royal Victoria Hospital, Montreal, Quebec, Canada; and the Gene Expression Laboratory (R.M.E., H.M.S.), Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, Calif.

Correspondence to Dr Henry M. Sucov, Institute for Genetic Medicine, Department of Cell and Neurobiology, University of Southern California School of Medicine, 2250 Alcazar St, IGM 240, Los Angeles, CA 90033. E-mail sucov{at}zygote.hsc.usc.edu

Abstract Several aspects of normal cardiovascular development require signaling by the vitamin A metabolite retinoic acid. We have previously established germ-line mutations in mice in the genes that encode the RAR1, RARß, and RXR retinoic acid receptors as a means of studying the function of these receptors in vivo. Although mutation of RXR results in fetal ventricular defects, the RAR1 and RARß mutations are apparently nonphenotypic in the heart and elsewhere. In this study, we have established and analyzed combinations of these receptor gene mutations. Malformations of the ventricular chamber (chamber hypoplasia and muscular ventricular septal defects), conotruncus (double-outlet right ventricle, transposition, and membranous ventricular septal defects), aortic sac (persistent truncus arteriosus and aorticopulmonary window), and aortic arch–derived arteries were recovered in various combinations of the RAR1, RARß, and RXR gene mutations. Depending on the combination of receptor mutations, selective defects were obtained in specific cardiovascular compartments, suggestive of differential expression or function of each receptor within domains of the developing heart.

Key Words: gene disruption • retinoid teratology • genetic deficiency • retinoid X receptor

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