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A transcriptionally silent RXRalpha supports early embryonic morphogenesis and heart development.

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 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.

SUBMITTER: Mascrez B

PROVIDER: S-EPMC2657455 | biostudies-other | 2009 Mar

REPOSITORIES: biostudies-other

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A transcriptionally silent RXRalpha supports early embryonic morphogenesis and heart development.

Mascrez Bénédicte B Ghyselinck Norbert B NB Chambon Pierre P Mark Manuel M

Proceedings of the National Academy of Sciences of the United States of America 20090302 11

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 ...[more]

PMID: 19255444

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Project description:BACKGROUND: Important knowledge about the role of vitamin A in vertebrate heart development has been obtained using the vitamin A-deficient avian in ovo model which enables the in vivo examination of very early stages of vertebrate heart morphogenesis. These studies have revealed the critical role of the vitamin A-active form, retinoic acid (RA) in the regulation of several developmental genes, including the important growth regulatory factor, transforming growth factor-beta2 (TGF?2), involved in early events of heart morphogenesis. However, this in ovo model is not readily available for elucidating details of molecular mechanisms determining RA activity, thus limiting further examination of RA-regulated early heart morphogenesis. In order to obtain insights into RA-regulated gene expression during these early events, a reliable in vitro model is needed. Here we describe a cell culture that closely reproduces the in ovo observed regulatory effects of RA on TGF?2 and on several developmental genes linked to TGF? signaling during heart morphogenesis. RESULTS: We have developed an avian heart forming region (HFR) cell based in vitro model that displays the characteristics associated with vertebrate early heart morphogenesis, i.e. the expression of Nkx2.5 and GATA4, the cardiogenesis genes, of vascular endothelial growth factor (VEGF-A), the vasculogenesis gene and of fibronectin (FN1), an essential component in building the heart, and the expression of the multifunctional genes TGF?2 and neogenin (NEO). Importantly, we established that the HFR cell culture is a valid model to study RA-regulated molecular events during heart morphogenesis and that the expression of TGF?2 as well as the expression of several TGF?2-linked developmental genes is regulated by RA. CONCLUSIONS: Our findings reported here offer a biologically relevant experimental in vitro system for the elucidation of RA-regulated expression of TGF?2 and other genes involved in vertebrate early cardiovascular morphogenesis.

Project description:BackgroundPlacental heart development and embryonic heart development occur in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor placentation has been associated with congenital heart disease, an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to congenital heart disease remain unresolved.MethodsIn this study, we use an in vivo neutrophil-driven placental inflammation model through antibody depletion of maternal circulating neutrophils at key stages during time-mated murine pregnancy: embryonic days 4.5 and 7.5. Pregnant mice were culled at embryonic day 14.5 to assess placental and embryonic heart development. A combination of flow cytometry, histology, and bulk RNA sequencing was used to assess placental immune cell composition and tissue architecture. We also used flow cytometry and single-cell sequencing to assess embryonic cardiac immune cells at embryonic day 14.5 and histology and gene analyses to investigate embryonic heart structure and development. In some cases, offspring were culled at postnatal days 5 and 28 to assess any postnatal cardiac changes in immune cells, structure, and cardiac function, as measured by echocardiography.ResultsIn the present study, we show that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. Consequently, placental inflammatory monocytes of maternal origin become capable of migration to the embryonic heart and alter the normal composition of resident cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Last, we show that tempering placental inflammation can prevent this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life.ConclusionsTaken together, these observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development, which has major implications on cardiac function into adult life.

Dataset Information

A transcriptionally silent RXRalpha supports early embryonic morphogenesis and heart development.

Publications

A transcriptionally silent RXRalpha supports early embryonic morphogenesis and heart development.

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