title: Regulation of the human endogenous retroviral Syncytin-1 and cell-cell fusion by the nuclear hormone receptors PPARγ/RXRα in placentogenesis.
abstract: Cytotrophoblast (CT) cell fusion into a syncytiotrophoblast is obligatory for placentation and mediated by the human endogenous retrovirus (HERV)-W envelope gene Syncytin-1. Abnormal placentation is associated with preeclampsia (PE), HELLP and intrauterine growth restriction (IUGR). In placentogenesis, the MAP-kinase p38α regulates PPARγ/RXRα signaling and target genes, like leptin, resistin, ABCG2, and hCG. The aim of this study was to analyze PPARγ/RXRα signaling and target gene regulation using primary CT cultures, the trophoblastic cell line BeWo and placental tissues from patients with normal and abnormal placentation. CT from four different human control placentae and BeWo cells demonstrated that Syncytin-1, other signaling members and CT cell fusions were regulated with PPARγ/RXRα activators troglitazone and 9-cis retinoic acid, via protein kinase A and p38α inhibition. Significant discordant regulations between CTs and BeWo were found. Two PPARγ/RXRα-response-elements from upstream regulatory elements and the 5'LTR of HERV-W were confirmed with DNA-protein binding assays using nuclear extracts and recombinant PPARγ/RXRα proteins. These promoter elements were validated with luciferase assays in the presence of PPARγ/RXRα modulators. Furthermore, troglitazone or 9-cis retinoic acid treatment of siRNA-PPARγ and siRNA-RXRα transfected BeWo cells proved the requirement of these proteins for Syncytin-1 regulation. Thirty primary abnormal placentae from PE, HELLP and IUGR patients compared to 10 controls showed significant deregulation of leptin RNA and protein, p38α, phospho-p38α, PPARγ, ABCG2, INSL4 and Syncytin-1. Our study characterized PPARγ/RXRα signaling in human CT and cell fusions identifying Syncytin-1 as a new target gene. Based on these results, a disturbed PPARγ/RXRα pathway could contribute to pathological human pregnancies.
authors.affiliation: Department of Gynaecology and Obstetrics, University-Clinic Erlangen, Erlangen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ruebner
authors.forename: Manuela
authors.initials: M
authors.lastname: Langbein
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Strissel
authors.forename: Christine
authors.initials: C
authors.lastname: Henke
authors.forename: Doreen
authors.initials: D
authors.lastname: Schmidt
authors.forename: Tamme W
authors.initials: TW
authors.lastname: Goecke
authors.forename: Florian
authors.initials: F
authors.lastname: Faschingbauer
authors.forename: Ralf L
authors.initials: RL
authors.lastname: Schild
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.forename: Reiner
authors.initials: R
authors.lastname: Strick
mesh_terms: D000077556:Alitretinoin; D002459:Cell Fusion; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D020077:Endogenous Retroviruses / Q000235:genetics; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D015686:Gene Products, env / Q000378:metabolism*; D017359:HELLP Syndrome / Q000378:metabolism / Q000473:pathology; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism; D010929:Placentation / Q000502:physiology*; D011225:Pre-Eclampsia / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D020218:Response Elements / Q000235:genetics; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D000077288:Troglitazone; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D002839:Chromans; D015686:Gene Products, env; D047495:PPAR gamma; D011257:Pregnancy Proteins; D034741:RNA, Small Interfering; D047490:Retinoid X Receptor alpha; D045162:Thiazolidinediones; C405335:syncytin; D000077556:Alitretinoin; D014212:Tretinoin; D017868:Cyclic AMP-Dependent Protein Kinases; D048308:Mitogen-Activated Protein Kinase 14; D000077288:Troglitazone