A transcriptionally silent RXRalpha supports early embryonic morphogenesis and heart development

Retinoic acid (RA) receptors (RARs) α, β, and γ heterodimerized with rexinoid receptors (RXRs) α, β, and γ mediate the RA signal. To analyze the contribution of the transcriptional activity of RXRα, the main RXR during embryogenesis, we have engineered a mouse line harboring a transcriptionally silent RXRα 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 RXRα 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 RXRα can act as a transcriptionally silent heterodimerization partner. Similarly, a transcriptionally silent RXRα 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 RXRα 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 RXRα.