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Endoglin (CD105) Expression Is Regulated by the Liver X Receptor Alpha (NR1H3) in Human Trophoblast Cell Line JAR¹

CNRS UMR6247-GreD,³ Centre de Recherche en Nutrition Humaine d'Auvergne,⁴ Clermont Université, 63177 Aubière, France Centro de Investigaciones Biologicas,⁵ Consejo Superior de Investigaciones Cientificas (CSIC), and Center for Biomedical Research on Rare Diseases (CIBERER), 28040 Madrid, Spain

ABSTRACT

Human implantation involves invasion of the uterine wall and remodeling of uterine arteries by extravillous cytotrophoblasts. Defects in these early steps of placental development lead to poor placentation and are often associated with preeclampsia, a frequent complication of human pregnancy. One of the complex mechanisms controlling trophoblast invasion involves the activation of the liver X receptor beta (or NR1H2, more commonly known as LXRbeta) by oxysterols known as potent LXR activators. This activation of LXRbeta leads to a decrease of trophoblast invasion. The identification of new target genes of LXR in the placenta could aid in the understanding of their physiological roles in trophoblast invasion. In the present study, we show that the endoglin (ENG) gene is a direct target of the liver X receptor alpha (NR1H3, also known as LXRalpha). ENG, whose gene is highly expressed in syncytiotrophoblasts, is part of the transforming growth factor (TGF) receptor complex that binds several members of the TGFbeta superfamily. In the human placenta, ENG has been shown to be involved in the inhibition of trophoblast invasion. Treatment of human choriocarcinoma JAR cells with T0901317, a synthetic LXR-selective agonist, leads to a significant increase in ENG mRNA and protein levels. Using transfection and electrophoretic mobility shift assays, we demonstrate that LXR (as a heterodimer with the retinoid X receptor) is able to bind the ENG promoter on an LXR response element and mediates the activation of ENG gene expression by LXRalpha in JAR cells. This study suggests a novel mechanism by which LXR may regulate trophoblast invasion in pathological pregnancy such as preeclampsia.

endoglin, gene regulation, human syncytiotrophoblast, implantation, liver X receptor, LXR, oxysterols, syncytiotrophoblast

¹Supported by grants from the Centre National de la Recherche Scientifique, the Université Blaise Pascal, the Fondation Danone, the Fondation pour la Recherche Médicale INE2000-407031/1, and the Fondation BNP-Paribas. K.M. is a recipient of a doctoral fellowship from the Ministère de l'Education Nationale de Recherche et de la Technologie. C.B. is supported by grants from Ministerio de Educacion y Cienza of Spain (SAF2004-01390 and SAF2007-61827).

Correspondence: ²Jean-Marc Lobaccaro, CNRS UMR6247 and Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont Université, 24 avenue des Landais, 63177 Aubière, France. FAX: 33 473 407 042; e-mail: j-marc.lobaccaro{at}univ-bpclermont.fr