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 trophoblast stem cell lines and extraembryonic ectoderm, and genetic ablation of ERR beta 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 beta 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.
Tremblay
G B
GB
Department of Research and Development, SignalGene, Inc., Montréal, Québec H2M 2N9, Canada.
Kunath
T
T
Bergeron
D
D
Lapointe
L
L
Champigny
C
C
Bader
J A
JA
Rossant
J
J
Giguère
V
V
D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects; D002522:Chlorocebus aethiops; D004054:Diethylstilbestrol / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D005043:Etiocholanolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005470:Fluorometry; D017930:Genes, Reporter; D005865:Gestational Age; D015726:Giant Cells / Q000473:pathology; D008024:Ligands; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D015394:Molecular Structure; D051958:Nuclear Receptor Coactivator 2; D010920:Placenta / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D011280:Pregnanolone / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013234:Stem Cells / Q000187:drug effects* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014327:Trophoblasts / Q000187:drug effects* / Q000473:pathology; D000097983:ERRalpha Estrogen-Related Receptor
D004054:Diethylstilbestrol; D004958:Estradiol; D004968:Estrogens, Non-Steroidal; D005043:Etiocholanolone; D005346:Fibroblast Growth Factors; D008024:Ligands; D008156:Luciferases; D051958:Nuclear Receptor Coactivator 2; D011280:Pregnanolone; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C098925:Esrrb protein, mouse; C107914:estrogen receptor-related receptor beta; C112971:fibroblast growth factor 14; C006576:androstane-3,17-dione