Uterine receptivity, the ability of the uterus to accept embryo implantation, is dependent upon ovarian steroid signaling which coordinates the paracrine crosstalk between the epithelial and stromal compartments of the endometrium. The ovarian steroid Progesterone, P4, acting through its cognate receptor, Pgr (mouse), is critical in the regulation of the compartmental crosstalk. During pregnancy, Pgr is expressed in the uterine epithelial for a finite period prior to embryo attachment. In humans, alteration in the PGR signaling is associated with endometrial diseases, such as infertility, endometriosis, and endometrial cancer. Hyperstimulation of PGR is associated with pregnancy failure after in vitro fertilization and embryo transfer, IVF/ET. The goal of this proposal is to investigate the molecular mechanisms regulated by Pgr and how they function in the regulation of uterine receptivity and disease. Utilizing Chromatin Immunoprecipitation combined with whole genome sequencing, ChIP-Seq, we have identified the binding sites of Pgr in the murine genome and have identified the transcription factor Sox17 as a Pgr target and potential partner of Pgr in the regulation of uterine receptivity. The hypothesis of this proposal is that cell specific and temporl interactions of Pgr and Sox17 are critical for uterine receptivity and alterations in the expressio of Sox17 and Pgr will impair uterine function. This proposal will investigate the role of Sox17 in the regulation of mouse uterine function. We will then investigate the molecular interactions of Sox17 in the regulation of endometrial function. Finally, we will test the importance of the timing of Pgr regulated signaling in mouse uterine receptivity. Completion of the aims of this proposal will define the role of PR in the regulation of endometrial function and determine the functional interactions of PR with other transcription factors in the regulation of endometrial gene expression and function. This proposal will also determine the importance or the temporal expression of PR in the uterus. Understanding how altered expression of PR disrupts uterine function is critical in understanding how the uterus response to endocrine therapy.

Public Health Relevance

Diseases of the uterus, such as infertility, endometriosis and endometrial cancer are a result of altered responses of the uterus to progesterone. The goal of this proposal is to investigate how the hormone progesterone, acting though its receptor regulates the ability of the uterus to support embryo implantation and control processes that prevent diseases, such as endometriosis and endometrial cancer.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Yoshinaga, Koji
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Baylor College of Medicine
Anatomy/Cell Biology
Schools of Medicine
United States
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Hai, Lan; Szwarc, Maria M; He, Bin et al. (2018) Uterine function in the mouse requires speckle-type poz protein. Biol Reprod 98:856-869
Szwarc, Maria M; Hai, Lan; Gibbons, William E et al. (2018) Human endometrial stromal cell decidualization requires transcriptional reprogramming by PLZF. Biol Reprod 98:15-27
Szwarc, Maria M; Hai, Lan; Gibbons, William E et al. (2018) Retinoid signaling controlled by SRC-2 in decidualization revealed by transcriptomics Reproduction 156:387-395
Szwarc, Maria Magdalena; Hai, Lan; Gibbons, William E et al. (2018) Retinoid Signaling Controlled by SRC-2 in Decidualization Revealed by Transcriptomics. Reproduction :
Szwarc, Maria M; Kommagani, Ramakrishna; Putluri, Vasanta et al. (2018) Steroid Receptor Coactivator-2 Controls the Pentose Phosphate Pathway through RPIA in Human Endometrial Cancer Cells. Sci Rep 8:13134
Hai, Lan; Szwarc, Maria M; Wetendorf, Margeaux et al. (2018) A mouse model engineered to conditionally express the progesterone receptor-B isoform. Genesis 56:e23223
Szwarc, Maria M; Kommagani, Ramakrishna; Peavey, Mary C et al. (2017) A bioluminescence reporter mouse that monitors expression of constitutively active ?-catenin. PLoS One 12:e0173014
Peavey, Mary C; Reynolds, Corey L; Szwarc, Maria M et al. (2017) Three-Dimensional High-Frequency Ultrasonography for Early Detection and Characterization of Embryo Implantation Site Development in the Mouse. PLoS One 12:e0169312
Peavey, Mary C; Reynolds, Corey L; Szwarc, Maria M et al. (2017) A Novel Use of Three-dimensional High-frequency Ultrasonography for Early Pregnancy Characterization in the Mouse. J Vis Exp :
Camden, Alison J; Szwarc, Maria M; Chadchan, Sangappa B et al. (2017) Growth regulation by estrogen in breast cancer 1 (GREB1) is a novel progesterone-responsive gene required for human endometrial stromal decidualization. Mol Hum Reprod 23:646-653

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