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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 10 5017-5024
Copyright © 2001 by The Endocrine Society

Other Original Articles

PPAR{gamma}/RXR{alpha} Heterodimers Control Human Trophoblast Invasion

Anne Tarrade, Kristina Schoonjans, Laetitia Pavan, Johan Auwerx, Cécile Rochette-Egly, Danièle Evain-Brion and Thierry Fournier

INSERM, U-427, Faculté de Pharmacie (A.T., L.P., D.E.-B., T.F.), 75006 Paris, France; and Institut de Génétique et Biologie Moléculaire et Cellulaire, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/INSERM (K.S., J.A., C.R.-E.), 67404 Illkirch, France

Address all correspondence and requests for reprints to: Dr. Thierry Fournier, INSERM, U-427, Faculté de Pharmacie, 75006 Paris, France. E-mail: t.fournier{at}pharmacie.univ-paris5.fr

Abstract

The ligand-dependent nuclear receptors PPAR{gamma} and RXR{alpha}/ß were recently determined to be essential for murine placental development and trophoblast differentiation. In the current study we examined the expression and role of the PPAR{gamma}/RXR{alpha} heterodimers in human invasive trophoblasts. We first report that in human first trimester placenta, PPAR{gamma} and RXR{alpha} are highly expressed in cytotrophoblasts at the feto-maternal interface, especially in the extravillous cytotrophoblasts involved in uterus invasion. The coexpression of PPAR{gamma} and RXR{alpha} genes in extravillous cytotrophoblast nuclei were then confirmed by immunocytochemistry, immunoblot, and real-time quantitative PCR using cultured purified primary extravillous cytotrophoblasts. We next examined, using the extravillous cytotrophoblast culture model, the biological role of PPAR{gamma}/RXR{alpha} heterodimers in vitro, and we showed that both synthetic (rosiglitazone) and natural [15-deoxy-{delta}-(12,14)PGJ2] PPAR{gamma} agonists inhibit extravillous cytotrophoblast invasion in a concentration-dependent manner and synergize with pan-RXR agonists. Conversely, PPAR{gamma} or pan-RXR antagonists promoted extravillous cytotrophoblast invasion. Furthermore, the pan-RXR antagonist abolished the inhibitory effect of the PPAR{gamma} agonists. Together these data underscore an important function of PPAR{gamma}/RXR{alpha} heterodimers in the modulation of trophoblast invasion.




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