Project Summary Embryo implantation failure is a significant causal factor of infertility for women worldwide. Although advances in our understanding of oocyte and embryo development have improved pregnancy success rates, these rates remain unacceptably low due in part to an endometrium that is nonreceptive to the embryo. For successful implantation, endometrial receptivity and subsequent decidualization requires coordinated progesterone (P4) signaling in a cell-type specific manner. While the signature cellular events that underpin P4-driven uterine receptivity and decidualization are known, our knowledge of the pivotal mediators of P4 action in these processes is incomplete. This knowledge-deficiency is significant as nothing short of identifying the key early signals that underpin P4-driven uterine receptivity will address the current clinical limitations in diagnosing and treating a non-receptive uterus at the molecular level. To address this deficiency, we recently demonstrated that the promyelocytic leukemia zinc finger (PLZF) transcription factor is a direct target of the progesterone receptor (PGR) and is indispensable for P4-dependent decidualization of cultured human endometrial stromal cells (hESCs). As further translational support for a P4 mediator role for PLZF in the human endometrium, PLZF expression levels in human endometrial biopsies are significantly induced during the P4-dominant secretory phase of the human non-conception menstrual cycle. In the early pregnant mouse, Plzf is induced in the epithelial and stromal compartments of the receptive uterus and is strongly expressed in decidual cells with pregnancy progression. These findings support our hypothesis that PLZF (and its downstream transcriptional program) acts as a pivotal mediator of P4-dependent uterine receptivity and decidualization and does so in an endometrial cell-type specific manner. This hypothesis will be tested by three specific aims. Using a recently generated mouse model carrying a Plzf conditional allele, Specific Aim 1 will establish the in vivo importance of Plzf (and its transcriptional programs) in P4-dependent endometrial receptivity and decidualization. Dissecting the individual contributions of epithelial and stromal Plzf signaling in the murine endometrium during the periimplantation period will be a major focus of Specific Aim 2. We recently demonstrated that direct transcriptional repression of the early growth response 1 (EGR1) transcription factor by PLZF is required for hESC decidualization;; blocking this regulation impairs hESC decidualization. Prior to decidualization, however, EGR1 in pre-decidual hESCs is required for these cells to decidualize, suggesting that EGR1 “primes” the pre- dec...