The Role of Notch1 in Endometrial Receptivity and Decidualization

No other tissue in the body undergoes such a dynamic and extensive growth and remodeling in such a relatively short period of time, like the endometrium. In preparation for the possibility of implantation, endometrial stromal cells undergo waves of proliferation, remodeling, and terminal transdifferentiation that transform the endometrium into the decidua of pregnancy. A large body of evidence suggests that the Notch family of receptors transduce extracellular signals responsible for cell survival, cell proliferation, and differentiation, which are processes that underlie stromal cell fate in the endometrium. As such, we investigated the role of Notch1 in endometrial integrity and decidualization. Both in vivo administration of a gamma-secretase inhibitor, which inhibits Notch activity, and Notch1 specific uterine-ablation, utilizing a progesterone receptor Cre-mouse model, demonstrated decidualization failure following an artificial-decidualization reaction. Concomitant with a defective deciduoma, Notch1 inhibition decreased cellular proliferation and increased apoptosis, as evidenced by a decrease in cyclin-D and other G1/S checkpoint components, an increased expression of the executor of apoptosis, caspase-3 and Bad, and a reduction in anti-apoptotic Bcl2 expression, in stromal cells. Microarray analysis revealed 3,655 genes that were affected by Notch1 ablation during decidualization, including multiple uterine-specific gene pathways, which include estrogen receptor signaling, TGFβ signaling, and the actin cytoskeletal pathway. In a baboon model of stimulated pregnancy, in vivo infusion of the embryonic hormone, chorionic gonadotropin (CG), induced Notch1 in the stromal component of the endometrium during the window of uterine receptivity, suggesting an interaction between CG and Notch1. To address this possible relationship, we utilized primary human endometrial stromal fibroblasts (HuF). CG induced Notch1 in both a time and dose-dependent manner. Furthermore, treatment with the ovarian hormone, progesterone in the presence of CG increased transcriptionally competent Notch1. Steroid-dependent Notch1 induction in the endometrial stroma was confirmed when a progesterone receptor antagonist inhibited Notch1 expression both in vivo and in vitro. A tightly regulated dialogue between a hormone-primed endometrium and a free-floating blastocyst is essential for successful implantation. In the endometrium, conceptus-mediated down regulation of the Notch receptor, an endometrial arbitrator of cell fate modulated the decidual response. These studies demonstrate that initially Notch mediates a survival signal, in the uterine endometrium, in response to hormones from the implanting blastocyst and the ovary, averting endometrial sloughing/menstruation. Subsequently, Notch1 acts as an inhibitor of differentiation during the decidualization of stromal fibroblasts. Our data in mice, baboon, and human models indicates that Notch1 plays a central role in preventing stromal fibroblasts from undergoing apoptosis and initiating decidualization by synergizing with progesterone. These studies demonstrate a central role for Notch1 in regulating stromal cell differentiation and suggest that Notch1 is critical for decidualization.