Regulation and role of PAX8 in decidualizing endometrial stromal cells

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The endometrium is the inner lining of the uterus. Monthly during the menstrual cycle and also throughout pregnancy, it is the site of an intense remodelling. The cellular and molecular mechanisms involved in this remodelling, however, are only partially understood. We have established a long-term research program dedicated to the investigation of these mechanisms, aiming to gain a better understanding of endometrium remodelling and normal reproductive function. In the short term, we plan to examine an endometrial remodelling process which is crucial for successful implantation of the embryo in the uterus and for maintenance of pregnancy, called decidualization. During this process, one type of cells in the endometrium, the endometrial stromal cells (ESCs), undergo a series of changes: they must differentiate into decidual cells, and at the same time acquire the ability to survive to various death-inducing signals. p53 and PAX8, two intracellular factors, accumulate in ESCs during decidualization; however, the precise regulation of their expression and their role in this context are unclear. Based on previous studies and on our preliminary results, it can be hypothesized that PAX8 activity dictates ESC integrity and function during decidualization, in a p53-dependent manner. We have a unique opportunity to verify this hypothesis using a model of decidualization in the rat, which closely mimics the decidualization process in humans. Using this rat model, we propose to investigate if: 1) PAX8 expression and activity is positively regulated by PKA activity in ESCs and is increased at the beginning of cAMP-induced decidualization; 2) PAX8 regulates p53 gene expression and promotes its accumulation in decidualizing ESCs; 3) this PAX8-p53 axis regulates survival and differentiation of ESCs at the time of decidualization. These studies should allow us to identify for the first time a role for PAX8 as a key regulator of ESC decidualization, and to uncover its p53-dependent mode of action. This represents an important initial step towards a thorough comprehension of the mechanisms underlying normal endometrial remodelling and reproductive function.