Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERR beta

The orphan nuclear receptor ERR beta is expressed in undifferentiated troph oblast stem cell lines and extraembryonic ectoderm, and genetic ablation of ERR beta results in abnormal trophoblast proliferation and precocious diff erentiation toward the giant cell lineage. Here, we show that the synthetic estrogen diethylstilbestrol (DES) promotes coactivator release from ERR be ta and inhibits its transcriptional activity. Strikingly, treatment of trop hoblast stem cells with DES led to their differentiation toward the polyplo id giant cell lineage. In addition, DES-treated pregnant mice exhibited abn ormal early placenta development associated with an overabundance of tropho blast giant cells and an absence of diploid trophoblast. These results defi ne a novel pathway for DES action and provide evidence for steroidlike cont rol of trophoblast development.