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The Peroxisome Proliferator-Activated Receptor Gamma Regulates Trophoblast Cell Differentiation in Mink (Mustela vison)¹

Centre of Animal Reproduction Research,³ Université de Montréal, Québec, Canada J2S 7C6 Department of Pediatrics,⁴ The Division of Reproductive and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37232

ABSTRACT

Nuclear receptors of the peroxisome proliferator-activated receptor (PPAR) family are implicated in implantation and early placental formation. In carnivores, the trophoblast invades to develop intimate contact with the endothelial cells of the maternal circulation, resulting in an endothelio-chorial form of placentation. Spatio-temporal investigation demonstrated that peroxisome proliferator-activated receptor gamma (PPARG) was strongly and specifically expressed in the mink trophoblast at the time of formation of the syncytiotrophoblast during early implantation, and in trophoblast of the placental labyrinth. The retinoid-X-receptor alpha (RXRA), the heterodimeric partner of PPARG in transcriptional regulation, is, with very few exceptions, co-expressed with PPARG in mink trophoblast. We used mink trophoblast cell lines together with a natural (15-deoxy-delta^12,14-prostaglandin J₂ ) or a synthetic (troglitazone) PPARG ligand to demonstrate that PPARG is an authentic regulator of gene expression in this tissue. Ligand-activated PPARG stimulated transcription of the PPRE-luc reporter gene transfected into these cell lines. The prostaglandin-induced morphologic changes were accompanied by attenuation in cell proliferation, an increase in PPARG mRNA and protein levels, and the appearance of enlarged and multinuclear cells. Furthermore, 15-deoxy-delta^12,14-prostaglandin J₂ stimulated the expression of invasion-related genes in trophoblast cells, namely, adipophilin and osteopontin. The results demonstrate that PPARG ligands attenuate proliferation and induce differentiation of mink trophoblast cells to the multlinuclear phenotype. The upregulation of differentiation-specific genes in the placenta under the influence of PPARG ligands provides a mechanism by which blastocyst and endometrial prostanoids regulate implantation, as well as the formation and maintenance of the placenta.

embryo, endotheliochorial placenta, implantation, placenta, PPARG, syncytiotrophoblast, trophoblast

¹Supported by a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada to B.D.M.; J.A.D., F.L.L., H.Z, S.K.D., and B.D.M. have no real or potential conflicts of interest to declare with entities related to the material being published.

Correspondence: ²Bruce D. Murphy, 3200 Sicotte, St-Hyacinthe, QC, Canada J2S 7C6. FAX: 450 778 8103; e-mail: bruce.d.murphy{at}umontreal.ca