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 J(2) ) 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 J(2) 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.