Cadherin-11 and cadherin-6 may play a central role in the formation and organization of the human endometrium and placenta.

The cadherins are key morphoregulators. A switch in the cadherin subtype(s) expressed by a population of cells has been associated with the differentiation and formation of tissues during embryonic development. To date, the role(s) of the cadherins in the highly regulated remodeling processes which occur in the human endometrium in preparation for the implanting embryo remain poorly characterized. Here we report that two atypical cadherins, known as cadherin‐6 and cadherin‐11, are spatiotemporally expressed in the human endometrium during the menstrual cycle. Cadherin‐6 levels are high in both the glandular epithelium and stroma of the endometrium during the follicular phase and decline as the cycle enters the luteal phase. The down‐regulation of cadherin‐6 in the glandular epithelium during the luteal phase does not effect the levels of cadherin‐11 in this cell type. In contrast, the loss of cadherin‐6 expression in endometrial stroma cells is concomitant with an increase in the levels of cadherin‐11. Collectively, these observations suggest that multiple factors regulate the expression of these two endometrial cadherins. As a first step in identifying these factors, we examined the effects of progesterone on cadherin‐6 and cadherin‐11 expression in isolated endometrial stromal cells. Progesterone was capable of differentially regulating the expression of these two stromal cell adhesion molecules. These findings lend further support to our hypothesis that steroids are key regulators of cadherin expression in mammalian tissues. Dev. Dyn. 1998;211:238‐247. © 1998 Wiley‐Liss, Inc.

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The cadherins play key roles in the formation and organization of the mammalian placenta by mediating cellular interactions and the terminal differentiation of trophoblastic cells. Although cadherin function is regulated by the cytoplasmic proteins, known as the catenins, the identity and expression pattern(s) of the catenins present in the trophoblastic cells of the human placenta have not been characterized. In these studies, we have determined that alpha-, beta-, gamma-catenin, and p120(ctn) expression levels are high in villous cytotrophoblasts isolated from the human term placenta but decline as these cells undergo aggregation and fusion to form syncytium with time in culture. In contrast, the expression levels of these four catenin subtypes remained constant in non-fusing JEG-3 choriocarcinoma cells at all of the time points examined in these studies. alpha-, beta-, gamma-catenin, and p120(ctn) expression was further immunolocalized to the mononucleate cells present in these two trophoblastic cell cultures. Similarly, intense immunostaining for all four catenins was detected in the mononucleate villous cytotrophoblasts of the human first trimester placenta. Collectively, these observations demonstrate that the expression levels of alpha-, beta-, gamma-catenin, and p120(ctn) are tightly regulated during the formation of multinucleated syncytium in vitro and in vivo.

The cellular mechanisms by which steroids and antisteroidal compounds modulate the function and/or integrity of the human endometrium remain poorly understood. We recently determined that the expression of the novel cadherin subtype, known as cadherin‐11, is tightly regulated in endometrial stromal cells undergoing decidualisation in vivo and in vitro. To determine whether the actions of antisteroids on the endometrium are mediated, at least in part, by their ability to regulate the expression of this cell adhesion molecule, we examined the effects of the antiprogestin RU486 and the antiestrogen ICI 182,780 on cadherin‐11 mRNA and protein expression levels in human endometrial stromal cells undergoing decidualisation in vitro. RU486 decreased the levels of the cadherin‐11 mRNA transcript and protein species present in these cell cultures in a dose‐ and time‐dependent manner. Similarly, ICI 182,780 was capable of reducing stromal cadherin‐11 mRNA and protein expression levels in a dose‐dependent manner, suggesting that the progesterone‐mediated increase in cadherin‐11 expression levels in human endometrial cells undergoing decidualisation in vitro is dependent on the presence of estrogens. Cadherin‐11 expression levels also were reduced in endometrial stromal cell cultures subjected to progesterone withdrawal, an in vitro model for menstrual breakdown. These studies not only give us useful insight into the mechanism(s) by which progesterone regulates stromal cadherin‐11 expression, but they strengthen our hypothesis that this cell adhesion molecule plays a central role in the remodeling processes that occur in the human endometrium in response to fluctuations in the levels of gonadal steroids. Mol. Reprod. Dev. 53:384–393, 1999. © 1999 Wiley‐Liss, Inc.