title: Decreased epithelial progesterone receptor A at the window of receptivity is required for preparation of the endometrium for embryo attachment.
abstract: The precise timing of progesterone signaling through its cognate receptor, the progesterone receptor (PGR), is critical for the establishment and maintenance of pregnancy. Loss of PGR expression in the murine uterine epithelium during the preimplantation period is a marker for uterine receptivity and embryo attachment. We hypothesized that the decrease in progesterone receptor A (PGRA) expression is necessary for successful embryo implantation. To test this hypothesis, a mouse model constitutively expressing PGRA (mPgrALsL/+) was generated. Expression of PGRA in all uterine compartments (Pgrcre) or uterine epithelium (Wnt7acre) resulted in infertility with defects in embryo attachment and stromal decidualization. Expression of critical PGRA target genes, indian hedgehog, and amphiregulin (Areg), was maintained through the window of receptivity while the estrogen receptor target gene, the leukemia inhibitory factor (Lif), a key regulator of embryo receptivity, was decreased. Transcriptomic and cistromic analyses of the mouse uterus at day 4.5 of pregnancy identified an altered group of genes regulating molecular transport in the control of fluid and ion levels within the uterine interstitial space. Additionally, LIF and its cognate receptor, the leukemia inhibitory factor receptor (LIFR), exhibited PGR-binding events in regions upstream of the transcriptional start sites, suggesting PGRA is inhibiting transcription at these loci. Therefore, downregulation of the PGRA isoform at the window of receptivity is necessary for the attenuation of hedgehog signaling, transcriptional activation of LIF signaling, and modulation of solutes and fluid, producing a receptive environment for the attaching embryo.
authors.affiliation: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.|Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Margeaux
authors.initials: M
authors.lastname: Wetendorf
authors.affiliation: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, USA.
authors.forename: San-Pin
authors.initials: SP
authors.lastname: Wu
authors.affiliation: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, USA.
authors.forename: Xiaoqiu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, USA.
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Rainer B
authors.initials: RB
authors.lastname: Lanz
authors.affiliation: Department of Obstetrics and Gynaecology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Leen
authors.initials: L
authors.lastname: Blok
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Sophia Y
authors.initials: SY
authors.lastname: Tsai
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tsai
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
authors.affiliation: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, USA.
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
mesh_terms: D000483:Alleles; D000818:Animals; D003001:Cloning, Molecular; D015536:Down-Regulation; D010064:Embryo Implantation; D004717:Endometrium; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D011374:Progesterone / Q000378:metabolism*; D053606:Receptors, OSM-LIF / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D053606:Receptors, OSM-LIF; D011980:Receptors, Progesterone; D051153:Wnt Proteins; C490508:Wnt7a protein, mouse; C101118:progesterone receptor A; D011374:Progesterone
keywords: progesterone receptor; implantation; uterine receptivity; progesterone signaling; mouse models