Female Reproductive Tract

Different Regulatory Pathways of Endometrial Connexin Expression: Pre-implantation Hormonal Mediated Pathway Versus Embryo Implantation Initiated Pathway

Abstract
Transformation of the endometrium into the receptive phase is under the control of ovarian steroid hormones and is in addition modulated by embryonic signals during implantation. We could previously show that this differentiation process is accompanied by a suppression of gap junction connexins(Cx) Cx26 and Cx43 prior to implantation followed by a local induction of both connexins in the implantation chamber. Here we demonstrate that connexin gene expression in the rodent endometrium is regulated via two distinct signaling pathways during these different stages of early pregnancy. During preimplantation transcription of connexins can be induced by estrogen via an estrogen receptor(ER)-dependent pathway. Additionally, Cx26 and Cx43 are induced by embryonic signals during implantation and delayed implantation as well as during artificially induced decidualization. In contrast to the estrogen induced expression, this embryonic/decidual associated induction of Cx26 and Cx43 could not be blocked by antiestrogen, thus pointing to another regulatory pathway independent of the ER. Studies in ER (ERKO) and ER (ERKO) knockout mice confirmed these different pathways demonstrating that in the endometrium estrogen-mediated Cx26 gene induction, but not induction during decidualization, is dependent on functional ER. To evaluate potential embryonic signals regulating Cx26 expression, uteri of pseudopregnant animals were incubated with different mediators in an organ culture model, showing that catechol estrogen and mediators of the inflammatory cascade like PGF2 and Il-1 are able to induce Cx26 expression through the ER independent pathway. Thus the present study demonstrates that endometrial expression of Cx26 and Cx43 is induced via estrogen and ER during preimplantation, but then utilizes to an ER-independent signaling pathway during embryo implantation and decidualization.

Key words: Female Reproductive Tract • Estradiol receptor • Gene regulation • Implantation • Uterus

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