Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERRβ
- Gilles B. Tremblay1,
- Tilo Kunath2,3,
- Denis Bergeron1,
- Line Lapointe1,
- Céline Champigny4,
- Jo-Ann Bader4,
- Janet Rossant2,3, and
- Vincent Giguère4,5,6
- 1Department of Research and Development, SignalGene, Inc., Montréal, Québec H2M 2N9, Canada; 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada; 3Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; 4Molecular Oncology Group, McGill University Health Center, Montréal, Québec H3A 1A1, Canada; 5Departments of Biochemistry, Medicine, and Oncology, McGill University, Montréal, Québec H3A 1A1, Canada
Abstract
The orphan nuclear receptor ERRβ is expressed in undifferentiated trophoblast stem cell lines and extraembryonic ectoderm, and genetic ablation of ERRβ results in abnormal trophoblast proliferation and precocious differentiation toward the giant cell lineage. Here, we show that the synthetic estrogen diethylstilbestrol (DES) promotes coactivator release from ERRβ and inhibits its transcriptional activity. Strikingly, treatment of trophoblast stem cells with DES led to their differentiation toward the polyploid giant cell lineage. In addition, DES-treated pregnant mice exhibited abnormal early placenta development associated with an overabundance of trophoblast giant cells and an absence of diploid trophoblast. These results define a novel pathway for DES action and provide evidence for steroidlike control of trophoblast development.
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Footnotes
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↵6 Corresponding author.
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E-MAIL vgiguere{at}dir.molonc.mcgill.ca; FAX (514) 843-1478.
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Article and publication are at www.genesdev.org/cgi/doi/10.1101/gad.873401.
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- Received December 12, 2000.
- Accepted February 7, 2001.
- Cold Spring Harbor Laboratory Press
