Peroxisome proliferator-activated receptor gamma controls Muc1 transcription in trophoblasts.
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for placental development. Here, we show that the mucin gene Muc1 is a PPARgamma target, whose expression is lost in PPARgamma null placentas. During differentiation of trophoblast stem cells, PPARgamma is strongly induced, and Muc1 expression is upregulated by the PPARgamma agonist rosiglitazone. Muc1 promoter is activated strongly and specifically by liganded PPARgamma but not PPARalpha or PPARdelta. A PPAR binding site (DR1) in the proximal Muc1 promoter acts as a basal silencer in the absence of PPARgamma, and its cooperation with a composite upstream enhancer element is both necessary and sufficient for PPARgamma-dependent induction of Muc1. In the placenta, MUC1 protein is localized exclusively to the apical surface of the labyrinthine trophoblast around maternal blood sinuses, resembling its luminal localization on secretory epithelia. Last, variably penetrant maternal blood sinus dilation in Muc1-deficient placentas suggests that Muc1 regulation by PPARgamma contributes to normal placental development but also that the essential functions of PPARgamma in the organ are mediated by other targets.
Shalom-Barak
Tali
T
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
Nicholas
Jill M
JM
Wang
Yongxu
Y
Zhang
Xiaowen
X
Ong
Estelita S
ES
Young
Timothy H
TH
Gendler
Sandra J
SJ
Evans
Ronald M
RM
Barak
Yaacov
Y
D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D003433:Crosses, Genetic; D024202:Electrophoretic Mobility Shift Assay; D004742:Enhancer Elements, Genetic; D005260:Female; D005456:Fluorescent Dyes; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D018396:Mucin-1 / Q000235:genetics*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D000077154:Rosiglitazone; D013234:Stem Cells / Q000166:cytology; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*; D015854:Up-Regulation
D005456:Fluorescent Dyes; D007004:Hypoglycemic Agents; D008024:Ligands; D018396:Mucin-1; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D008156:Luciferases