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Vol. 15, No. 7, pp. 833-838, April 1, 2001
1 Department of Research and Development, SignalGene,
Inc., Montréal, Québec H2M 2N9, Canada; 2 Samuel Lunenfeld
Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5,
Canada; 3 Department of Medical Genetics and Microbiology,
University of Toronto, Toronto, Ontario M5S 1A8, Canada;
4 Molecular Oncology Group, McGill University Health Center,
Montréal, Québec H3A 1A1, Canada; 5 Departments of
Biochemistry, Medicine, and Oncology, McGill University, Montréal,
Québec H3A 1A1, Canada
The orphan nuclear receptor ERR
is expressed in
undifferentiated trophoblast stem cell lines and extraembryonic
ectoderm, and genetic ablation of ERR 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 ERR 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.
[Key Words:
Diethylstilbestrol; trophoblast; cell
differentiation; ERR]
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