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Cited by 88Reproductive System and PregnancyReproductive Biology and FertilityEstrogen and related hormone effects

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Decreased epithelial progesterone receptor A at the window of receptivity is required for preparation of the endometrium for embryo attachment†

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Wetendorf, Margeaux, Wu, San-Pin, Wang, Xiaoqiu, Creighton, Chad J., Wang, Tianyuan, Lanz, Rainer B., Blok, Leen, Tsai, Sophia Y., Tsai, Ming-Jer, Lydon, John P., DeMayo, Francesco J.·2017·Biology of Reproduction
DOI 10.1095/biolreprod.116.144410PMC PMC6225975
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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.

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Crossref · 10.1095/biolreprod.116.144410

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  • High Na+/Cl− and low K+ levels in utero can be detrimental to embryo attachment through establishment of an unfit, unreceptive uterine environment.

    “Recent studies have shown that high Na+/Cl− and low K+ levels in utero can be detrimental to embryo attachment through the establishment of an unfit, unreceptive uterine environment [50].”

    From Stress and the HPA Axis: Balancing Homeostasis and Fertility. (2017) · cites this paper as [50]

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Metadata

Authors
Wetendorf, M., Wu, S.-P., Wang, X., Creighton, C. J., Wang, T., Lanz, R. B., Blok, L., Tsai, S. Y., Tsai, M.-J., Lydon, J. P., & DeMayo, F. J.
Affiliations
  • Baylor College of Medicine (US)
  • National Institute of Environmental Health Sciences (US)
  • Erasmus MC (NL)
Corresponding author
DeMayo, Francesco J.
ORCID
Venue
Biology of Reproduction
Publisher
Oxford University Press (OUP)
Published
2017-01-24
Volume
96
Issue
2
Pages
313-326
ISSN
  • 0006-3363 (ISSN-L)
  • 1529-7268
DOI
10.1095/biolreprod.116.144410
PMC
PMC6225975
OpenAlex
W2588892416
Cited by
88
References
0
Citations by year
2026: 6 · 2025: 10 · 2024: 8 · 2023: 7 · 2022: 10 · 2021: 11 · 2020: 12 · 2019: 9 · 2018: 10 · 2017: 5
FWCI
4.46
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • Biology of Reproduction (publishedVersion, public-domain)
  • Europe PMC (PubMed Central) (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
Funders
National Institutes of Health
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
  • Health Sciences › Medicine › Reproductive Medicine › Reproductive Biology and Fertility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
Keywords
progesterone receptor A, endometrial receptivity, embryo implantation, endometrial preparation, uterine epithelium, decidualization, leukemia inhibitory factor, LIFR, Indian hedgehog, amphiregulin, Hedgehog signaling, transcriptional repression, infertility, mouse model
MeSH terms
Alleles, Animals, Cloning, Molecular, Endometrium, Female, Gene Expression Regulation, Male, Mice, Transgenic, Embryo Implantation, Progesterone, Receptors, Progesterone, Down-Regulation, Wnt Proteins, Receptors, OSM-LIF, Hedgehog Proteins

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