Hand2Controls Female Fertility by Critically Regulating Uterine Epithelial Proliferation and Stromal Differentiation During Embryo Implantation.

During early pregnancy, the attenuation of estrogen (E)-mediated proliferation of uterine epithelium by progesterone (P) is a prerequisite for successful embryonic implantation. Our recent studies revealed that the basic helix-loop-helix (bHLH) transcription factor Hand2 is induced in response to P signaling in uterine stroma at the time of implantation. To investigate the function of Hand2 in implantation, we created a conditional knockout of the Hand2gene in the uterus of adult mice by employing the Cre-LoxP strategy. Ablation of Hand2in the uterus led to female infertility due to the failure of embryos to attach to uterine epithelium. In the absence of Hand2, uterine epithelium remained proliferative and failed to transition to the receptive state that allows implantation. Our results revealed a unique mechanism in which P-induced expression of Hand2 in the uterine stromal compartment normally suppresses the production of several members of the fibroblast growth factor (FGF) family, which act as paracrine mediators of mitogenic effects of E on the epithelium. In mouse uteri lacking Hand2, continued induction of these FGFs in the stroma activates ERK/MAP kinase signaling, maintains epithelial proliferation, and stimulates E-induced pathways in this tissue that impair attachment of the embryo to the uterine epithelium. In normal pregnant mice, uterine expression of Hand2 continues in differentiating stromal cells surrounding the implanted embryo, suggesting a possible regulatory role of this factor in decidualization. Interestingly, the steroid hormone-primed stromal cells of the Hand2-ablated uteri were able to undergo proliferation in response to an artificial decidual stimulus. The Hand2-null stromal cells, however, failed to undergo terminal differentiation as indicated by the lack of expression of certain decidual biomarkers in these cells. Collectively, our findings identified Hand2 as a key mediator of P signaling in uterine stroma and established its role in controlling critical pathways that regulate uterine epithelial receptivity and stromal decidualization during implantation. (Supported by U54 HD055787 as part of the NICHD/NIH Centers Program in Reproduction and Infertility Research).(platform)