Endometrial stromal beta-catenin is required for steroid-dependent mesenchymal-epithelial cross talk and decidualization

Abstract

Background: Beta-catenin is part of a protein complex associated with adherens junctions. When allowed to accumulate to sufficient levels in its dephosphorylated form, beta-catenin serves as a transcriptional co-activator associated with a number of signaling pathways, including steroid hormone signaling pathways. Methods: To investigate the role of beta-catenin in progesterone (\(P_4\)) signaling and female reproductive physiology, conditional ablation of Ctnnb1 from the endometrial mesenchymal (i.e. stromal and myometrial), but not epithelial, compartment was accomplished using the Amhr2-Cre mice. Experiments were conducted to assess the ability of mutant female mice to undergo pregnancy and pseudopregnancy by or through oil-induced decidualization. The ability of uteri from mutant female mice to respond to estrogen (\(E_2\)) and \(P_4\) was also determined. Results: Conditional deletion of Ctnnb1 from the mesenchymal compartment of the uterus resulted in infertility stemming, in part, from complete failure of the uterus to decidualize. \(E_2\)-stimulated epithelial cell mitosis and edematization were not altered in mutant uteri indicating that the mesenchyme is capable of responding to \(E_2\). However, exposure of ovariectomized mutant female mice to a combined \(E_2\) and \(P_4\) hormone regimen consistent with early pregnancy revealed that mesenchymal beta-catenin is essential for indirectly opposing \(E_2\)-induced epithelial proliferation by \(P_4\) and in some mice resulted in development of endometrial metaplasia. Lastly, beta-catenin is also required for the induced expression of genes that are known to play a fundamental role in decidualization such as Ihh, Ptch1, Gli1 and Muc1. Conclusions: Three salient points derive from these studies. First, the findings demonstrate a mechanistic linkage between the \(P_4\) and beta-catenin signaling pathways. Second, they highlight an under appreciated role for the mesenchymal compartment in indirectly mediating \(P_4\) signaling to the epithelium, a process that intimately involves mesenchymal beta-catenin. Third, the technical feasibility of deleting genes in the mesenchymal compartment of the uterus in an effort to understand decidualization and post-natal interactions with the overlying epithelium has been demonstrated. It is concluded that beta-catenin plays an integral role in selective \(P_4\)-directed epithelial-mesenchymal communication in both the estrous cycling and gravid uterus.