A transcriptionally silent RXRα supports early embryonic morphogenesis and heart development

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Abstract
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 RXR alpha, the main RXR during embryogenesis, we have engineered a mouse line harboring a transcriptionally silent RXR alpha 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 RXR alpha 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 RXR alpha can act as a transcriptionally silent heterodimerization partner. Similarly, a transcriptionally silent RXR alpha 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 RXR alpha 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 RXR alpha.