Summary: The loss of uterine epithelial progesterone receptor (PGR) is crucial for successful embryo implantation in both humans and mice. The two major isoforms PGRA and PGRB have divergent functions under both physiological and pathological conditions. The present study compares phenotypes and gene signatures of PGRA and PGRB in uterine epithelium using uterine epithelial-specific constitutively expressed PGRA or PGRB mouse models. The cistrome and transcriptome analysis reveals substantial overlap between epithelial PGRA and PGRB, and both disrupt embryo implantation through FOXO1 pathways. Constitutive epithelial PGRA and PGRB expression impairs ESR1 occupancy at the promoter of Lif leading to reduced Lif transcription and further exaggerates SGK1 expression leading to enhanced PI3K-SGK1 activities, and both contribute to the decline of nuclear FOXO1 expression. Our study demonstrates that PGRA and PGRB in the uterine epithelium act on a similar set of target genes and commonly regulate the LIF-SGK1-FOXO1 signaling pathway for embryo implantation.
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