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FASEB J. 2018 Jul;32(7):3765-3781. doi: 10.1096/fj.201701038R. Epub 2018 Feb 15.

Retinoic acid signaling promotes the cytoskeletal rearrangement of embryonic epicardial cells.

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Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas, USA.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA.
Stowers Institute for Medical Research, Kansas City, Missouri, USA.
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, USA.
Conselho Nacional do Desenvolvimento Científico e Tecnológico (CNPq) Sao Paulo, Brazil; and.
Northern Ontario School of Medicine, Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario, Canada.


All- trans-retinoic acid (RA), a vitamin A metabolite, is an important signaling molecule required for the proper development of the heart. The epicardium is the main source of RA in the embryonic heart, yet the cardiogenic functions of epicardial-produced RA are not fully understood. Here, we investigated the roles of RA signaling in the embryonic epicardium using in vivo and in vitro models of excess or deficiency of RA. Our results suggested that RA signaling facilitates the cytoskeletal rearrangement required for the epicardial-to-mesenchymal transition of epicardial cells. In vivo treatment with an inhibitor of RA synthesis delayed the migration of epicardial-derived precursor cells (EPDCs) into the myocardium; the opposite was seen in the case of dehydrogenase/reductase superfamily (DHRS)3-deficient embryos, a mouse model of RA excess. Analysis of the behavior of epicardial cells exposed to RA receptor agonists or inhibitors of RA synthesis in vitro revealed that appropriate levels of RA are important in orchestrating the platelet-derived growth factor-induced loss of epithelial character, cytoskeletal remodeling, and migration, necessary for the infiltration of the myocardium by EPDCs. To understand the molecular mechanisms by which RA regulates epicardial cytoskeletal rearrangement, we used a whole transcriptome profiling approach, which in combination with pull-down and inhibition assays, demonstrated that the Ras homolog gene family, member A (RhoA) pathway is required for the morphologic changes induced by RA in epicardial cells. Collectively, these data demonstrate that RA regulates the cytoskeletal rearrangement of epicardial cells via a signaling cascade that involves the RhoA pathway.-Wang, S., Yu, J., Jones, J. W., Pierzchalski, K., Kane, M. A., Trainor, P. A., Xavier-Neto, J., Moise, A. R. Retinoic acid signaling promotes the cytoskeletal rearrangement of embryonic epicardial cells.


RhoA; cardiac development; cytoskeletal remodeling; retinoic acid; vitamin A


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