RESUMO
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.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Mucina-1/genética , PPAR gama/metabolismo , Transcrição Gênica , Trofoblastos/metabolismo , Animais , Sítios de Ligação , Células Cultivadas , Cruzamentos Genéticos , Ensaio de Desvio de Mobilidade Eletroforética , Elementos Facilitadores Genéticos , Feminino , Corantes Fluorescentes , Genes Reporter , Hipoglicemiantes/farmacologia , Ligantes , Luciferases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , PPAR gama/agonistas , Gravidez , Regiões Promotoras Genéticas , Rosiglitazona , Células-Tronco/citologia , Tiazolidinedionas/farmacologia , Trofoblastos/citologia , Regulação para CimaRESUMO
Targeting of the nuclear prostaglandin receptor peroxisome proliferator-activated receptor delta (PPARdelta) by homologous recombination results in placental defects and frequent (>90%) midgestation lethality. Surviving PPARdelta(-/-) mice exhibit a striking reduction in adiposity relative to wild-type levels. This effect is not reproduced in mice harboring an adipose tissue-specific deletion of PPARdelta, and thus likely reflects peripheral PPARdelta functions in systemic lipid metabolism. Finally, we observe that PPARdelta is dispensable for polyp formation in the intestine and colon of APC(min) mice, inconsistent with its recently proposed role in the establishment of colorectal tumors. Together, these observations reveal specific roles for PPARdelta in embryo development and adipocyte physiology, but not cancer.