Compartment-selective sensitivity of cardiovascular morphogenesis to combinations of retinoic acid receptor gene mutations.
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 RAR alpha 1, RAR beta, and RXR alpha retinoic acid receptors as a means of studying the function of these receptors in vivo. Although mutation of RXR alpha results in fetal ventricular defects, the RAR alpha 1 and RAR beta 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 RAR alpha 1, RAR beta, and RXR alpha 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.
Lee
R Y
RY
Department of Cell and Neurobiology, University of Southern California School of Medicine, Los Angeles 90033, USA.
Luo
J
J
Evans
R M
RM
Giguere
V
V
Sucov
H M
HM
D000818:Animals; D001011:Aorta / Q000002:abnormalities / Q000196:embryology; D001013:Aorta, Thoracic / Q000196:embryology; D002319:Cardiovascular System / Q000196:embryology*; D003330:Coronary Vessel Anomalies / Q000196:embryology / Q000235:genetics / Q000473:pathology; D005314:Embryonic and Fetal Development; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006351:Heart Valves / Q000196:embryology; D051379:Mice / Q000196:embryology; D008817:Mice, Mutant Strains; D009154:Mutation; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D014680:Veins / Q000196:embryology
D018168:Receptors, Retinoic Acid