Conditional Ablation of the Progesterone Receptor Specifically in the Uterine Epithelium Demonstrates Its Necessary Role in the Regulation of Uterine Function.

Abstract

Uterine progesterone receptor (PR), expressed in both the epithelium and stroma, mediates epithelial-stromal crosstalk during embryo implantation and pregnancy. Ex vivo tissue reconstitution studies have pointed to stromal PR as being critical for the regulation of uterine epithelial gene expression (i.e., Indian hedgehog (Ihh)) and inhibition of mitogenic estrogen (E2) action whereas the role of epithelial PR has been largely unexplored. Here, we investigated the vivo role of epithelial PR during pregnancy and in the regulation of epithelial gene expression using compartment-specific ablation of PR. Using the Wnt7a-Cre mouse model, PR was ablated specifically in the uterine epithelium. This ablation rendered female mice infertile, demonstrating that epithelial PR is critical for female fertility. We examined uterine function by assessing the ability of these mice to undergo the decidual response. The epithelial PR conditional knockout mice failed to display a decidual response indicating that, despite the presence of PR in the stroma, decidualization is unable to occur without epithelial PR. We next wanted to determine if epithelial PR may regulate the expression of progesterone (P4)-target genes. Epithelial PR is critical for P4-induction of epithelial P4-target genes (Ihh, Areg, Gata2, Cyp26a1), but not stromal P4-target genes (Il13ra2). Transfection analysis revealed that epithelial PR can transactivate Ihh gene expression in Hec1a cells further confirming its critical role in P4-target gene expression. Therefore, epithelial PR plays a critical role in epithelial P4-target gene expression which differs from previous observations using tissue reconstitution experiments. In the uterus, P4 inhibits E2 actions such as uterine weight gain, epithelial proliferation, and E2-target gene expression. Normal P4-inhibition of estrogen-induced weight gain was observed in these mice. However, examination of P4-inhibition of specific E2-target genes demonstrated that epithelial PR plays a gene-specific role in P4-inhibition exhibiting inhibition of Ltf and Clca3 expression, but not Lif expression. We are currently studying its potential role in P4-inhibition of E2-induced epithelial proliferation. In summary, using an in vivo mouse model, we have shown that epithelial PR is necessary for female fertility as a mediator of decidualization, P4-target gene expression, and the P4-inhibition of E2 action. This work was supported by NIH Grant RO1CA077530 (to J.P.L.) and R01HD042311 (to F.J.D.). (platform)