Constitutive expression of Progesterone Receptor B in the uterine epithelium prevents implantation by inhibiting estrogen regulation of LIF signaling [RNAseq-PRAoe_PRBoe_oil_P4]

RNA-seq analysis of uterine luminal epithelium at D4.5 indicates that epithelial PGRA and PGRB shares conseved pathways. Constitutive epithelial PGRA and PGRB disrupts the embryo implantation both through the suppressed FOXO1 signaling by excluding FOXO1 from the nuclear at the uterine epithelium. There are three layers of regulation. Firstly, PGRA and PGRB diminishes Lif transcription in uterine glands by blocking ESR1 binding at the Lif promoter at D3.5 which is critical for the FOXO1 nuclear expression at D4.5 through LIF/pSTAT3/FOXO1. Secondly, PGRA and PGRB directly suppres Foxo1 transcription at the uterine epithelium probably through direct binding at Foxo1 promoter. Thirdly, PGRA and PGRB promotes the Sgk1 transcription, the kinases that phosphorylate FOXO1 to translocate it into cytoplasma for degradation. PgrcrePgrALsL/+ and PgrcrePgrBLsL/+ mice were ovariectomized for 2 weeks. And the whole uterus were collected for RNA-Seq after 6h oil or progesterone treatment.