Signal Transducer and Activator of Transcription-3 Is Critical for Uterine Implantation and Decidualization.

Infertility rates in humans have increased to approximately 10-15% in recent years. A major cause of infertility is implantation failure. Decidualization, mediated by the ovarian steroids estrogen and progesterone, is required to sustain the post-implantation phase. Mitogen inducible gene 6 (Mig-6) is an essential mediator of progesterone receptor (PR) function in the uterus. Signal transducer and activator of transcription-3 (Stat3) has been identified as a MIG-6-associated molecule, and interaction of STAT3 with PR has been detected in decidual lysates. To identify the interaction of STAT3 with PR and MIG-6 and its effect on uterine function, we performed immunoprecipitation using transient co-transfection and mouse uteri treated with estrogen and progesterone. STAT3 interacted with PR-A and MIG-6 but not with PR-B. The interaction of STAT3 with MIG-6 was also identified by co-immunoprecipitation in uterine lysate of control mice but not in PRcre/+Mig-6f/f mice. These results indicate that STAT3, MIG-6 and PR-A form a complex and may regulate each other's function. Stat3 activation during the implantation period has been shown to be important for uterine receptivity and decidualization. However, research on the role of Stat3 has been restricted to transient Stat3 knockdown because Stat3-deficient mice are embryo lethal. Therefore, a Stat3 conditional knockout mouse model is critical for understanding the role of Stat3 in vivo. In order to investigate the role of Stat3 in uterine function, we have conditionally ablated Stat3 in the PR-positive cells (PRcre/+Stat3f/f; Stat3d/d). Female Stat3d/d mice developed normal uterine and ovarian morphology and structure. Ovulation and fertilization rate of Stat3d/d mice did not differ from control Stat3f/f mice. Stat3d/d mice have fertility defects. Analysis of the uterus on day 5.5 of pregnancy showed disrupted blastocyst implantation in Stat3d/d mice. Stat3d/d mice also showed a defect of the uterus to respond to the artificial induction of the decidual response. In conclusion, our study suggests that Stat3 regulates decidualization and implantation which is a requisite for fertility, through interaction of PR and Mig-6 in the mouse uterus. This work was supported by National Institutes of Health Grant R01HD057873.