MIG‐6 Plays a Critical Role as a PGR Mediator in Maintaining Epithelial and Stromal Cells for Uterine Receptivity

ABSTRACT Ovarian steroid hormones—estrogen and progesterone—play a central role in regulating epithelial‐stromal interactions in the uterus. These interactions are critical for uterine function, including endometrial receptivity, implantation, and decidualization. These interactions involve complex signaling crosstalk between the uterine epithelium and the underlying stroma, with dynamic cell population‐specific roles. Mitogen‐inducible gene 6 (MIG‐6) is a key mediator of progesterone signaling in the endometrium, and loss of MIG‐6 results in implantation failure due to a non‐receptive endometrium. To investigate whether MIG‐6 deficiency disrupts the complex and dynamic cell population‐specific roles of uterine cells, we performed single‐cell RNA sequencing to characterize the cellular composition and functional alterations in the non‐receptive endometrium of uterine‐specific Mig‐6 knockout ( Pgr cre/+ Mig‐6 f/f ; Mig‐6 d/d ) mice. Compared to control mice, Mig‐6 d/d mice exhibited distinct gene expression patterns in both endometrial epithelial and stromal cells. We identified dysregulation of Egr1 in the non‐receptive endometrium along with attenuated expression of Foxa2 and Cyp26A1 in epithelial cells of Mig‐6 d/d mice. Notably, LRP2 expression was diminished in epithelial cells of both Mig‐6 d/d mice and infertile women with endometriosis. These findings demonstrate that MIG‐6 is a critical progesterone receptor (PGR) mediator that maintains endometrial epithelial and stromal cell function essential to uterine receptivity. Our study advances the understanding of the molecular pathways underlying endometrial receptivity and provides a foundation for therapeutic strategies to improve pregnancy outcomes.