A transcriptionally silent RXRalpha supports early embryonic morphogenesis and heart development.
Retinoic acid (RA) receptors (RARs) alpha, beta, and gamma heterodimerized with rexinoid receptors (RXRs) alpha, beta, and gamma mediate the RA signal. To analyze the contribution of the transcriptional activity of RXRalpha, the main RXR during embryogenesis, we have engineered a mouse line harboring a transcriptionally silent RXRalpha mutant that lacks the activation functions AF1 and AF2. All homozygous mutants (Rxra(afo)) display the ocular defects previously observed in compound Rar-null and Rxra/Rar-null mutants, thus demonstrating that a transcriptionally active RXRalpha is required during eye development. In contrast, the vast majority of Rxra(afo) fetuses do not display the Rxra-null mutant hypoplasia of the myocardium, thus demonstrating that RXRalpha can act as a transcriptionally silent heterodimerization partner. Similarly, a transcriptionally silent RXRalpha mutant can support early embryogenesis, as Rxra(afo)/Rxrb-null embryos display a normal morphology, contrasting with the severe malformations exhibited by compound Rxra/Rxrb-null embryos. Along the same line, we show that a silent RXRalpha mutant is sufficient to allow the initial formation of the placental labyrinth, whereas later steps of trophoblast cell differentiation critically requires the AF2, but not the AF1, function of RXRalpha.
Mascrez
Bénédicte
B
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7104, Institut National de la Santé et de la Recherche Médicale U964, University Louis Pasteur de Strasbourg, France.
Ghyselinck
Norbert B
NB
Chambon
Pierre
P
Mark
Manuel
M
D000818:Animals; D004622:Embryo, Mammalian; D005123:Eye / Q000196:embryology / Q000254:growth & development; D005260:Female; D005838:Genotype; D006321:Heart / Q000196:embryology / Q000254:growth & development; D051379:Mice; D008817:Mice, Mutant Strains; D009024:Morphogenesis / Q000235:genetics*; D010920:Placenta / Q000166:cytology; D011247:Pregnancy; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D014158:Transcription, Genetic; D014327:Trophoblasts / Q000166:cytology
C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha