Signal transducer and activator of transcription‐3 (Stat3) plays a critical role in implantationviaprogesterone receptor in uterus

Abstract

Recent studies have shown that activation of the signal transducer and activator of transcription-3 (Stat3) is required for decidualization, interacting with progesterone receptor (PR) in uterus. Based on previous reports, we hypothesized that crosstalk between STAT3 and PR signaling is required for successful implantation. To identify the interaction between STAT3 and PR isoforms, we performed immunoprecipitation following transient cotransfection and found that STAT3 physically interacted with PR-A, which is known to be important for uterine development and function, but not with PR-B. To further investigate the role of Stat3 in uterine function, Stat3 was conditionally ablated only in the PR-positive cells (PR(cre/+) Stat3(f/f); Stat3(d/d)). Our studies revealed that ovarian function and uterine development of Stat3(d/d) mice were normal. However, Stat3(d/d) female mice were infertile due to defective embryo implantation. Unlike Stat3(f/f) mice, Stat3(d/d) mice exhibited an unclosed uterine lumen. Furthermore, uteri of Stat3(d/d) mice were unable to undergo a well-characterized hormonally induced decidual reaction. The expression of stromal PR was decreased during decidualization and preimplantation period in Stat3(d/d) mice, and PR target genes were significantly down-regulated after progesterone induction. Our results suggest that STAT3 and PR crosstalk is required for successful implantation in the mouse uterus.

Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization

“…Although there is no special indications that whether the polyploidization of stromal cells is existed, uterine Stat3 knockout are defective in hormonally induced decidual reaction, clearly with the absence of stromal cell polyploidization. 40 In summary, our results illustrate that E2F8 expression in stromal cells is regulated by progesterone through activating HB-EGF/EGFR/ERK/STAT3 signal pathway.…”

“…STAT3 had been tightly linked to implantation and decidualization in mice and humans. 40,41 Conditional ablation of Stat3 in mouse uterus results in embryo implantation failure. Although there is no special indications that whether the polyploidization of stromal cells is existed, uterine Stat3 knockout are defective in hormonally induced decidual reaction, clearly with the absence of stromal cell polyploidization.…”

Egr1 Protein Acts Downstream of Estrogen-Leukemia Inhibitory Factor (LIF)-STAT3 Pathway and Plays a Role during Implantation through Targeting Wnt4

“…LIF is an essential mediator of estrogen and can replace nidatory estrogen in the activation of delayed implantation (4). LIF activates the phosphorylation of transcription factor STAT3, which is also indispensable for implantation (12). As a previous study has shown two potential STAT3 binding sites in Egr1 promoter (31), we hypothesized that estrogen might control the expression of Egr1 through LIF-STAT3 pathway.…”

“…The stromal localization of LIF is similar to phosphorylated STAT3 expression pattern (10). Conditional knock-out or transient suppression of STAT3 results in implantation failure, which suggests the critical role of STAT3 during implantation (11)(12)(13)(14). As a pleiotropic cytokine, LIF is also essential for mouse and human decidualization (15,16).…”

Molecular determinants of uterine receptivity

“…This signaling pathway, including Stat3 nuclear translocation in the luminal and glandular epithelium, is attenuated in LIF null mutant uteri (Cheng et al, 2001). Recent studies further demonstrate that uterine conditional deletion of Stat3 also induces implantation failure (Lee et al, 2013, Pawar et al, 2013, Sun et al, 2013. In the human, a low level of LIF is associated with unexplained recurrent abortion and infertility (Hambartsoumian, 1998, Piccinni et al, 1998.…”