Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function

Franco, Heather L.; Rubel, Cory A.; Large, Michael J.; Wetendorf, Margeaux; Fernández-Valdivia, Rodrigo; Jeong, Jae Wook; Spencer, Thomas E.; Behringer, Richard R.; Lydon, John P.; DeMayo, Francesco J.

doi:10.1096/fj.11-193334

Cited by 137 publications

(124 citation statements)

References 47 publications

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“…Without functional P4 signaling, as seen in Pgr KO mice, pregnancy is unable to occur because of implantation and decidualization failure (29,30). In our study, the expression of Pgr is significantly decreased in N1ICD OEx mice compared with control mice, which correlates with the dramatic down-regulation of P4 target genes (Ihh, Nr2f2, Areg, Hoxa10, and Hand2) in both epithelial and stromal cells.…”

Section: Discussionsupporting

confidence: 48%

“…However, supplemental P4 can only rescue the expression of P4 target genes by 10-30% compared with the expression levels found in control mice. Dysregulated E2 signaling and E2-induced LE proliferation associated with infertility can result from a lack of P4 receptor and target gene expression, including Ihh, Nr2f2, and Hand2 (21,(29)(30)(31)(32). In our study, decreased P4 signaling is associated with abnormally up-regulated E2 signaling in uterine epithelial cells of OEx mice as evidenced by increased expression of Esr1 and its phosphorylated form p-Esr1; up-regulation of target genes Muc1, Muc4, Ltf, and C3; and the increased proliferation of epithelial cells, which is driven by E2 signaling.…”

Section: Discussionmentioning

confidence: 99%

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Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility

Strug

Jeong

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In mammalian reproduction, implantation is one of the most critical events. Failure of implantation and the subsequent decidualization contribute to more than 75% of pregnancy losses in women. Our laboratory has previously reported that inhibition of Notch signaling results in impaired decidualization in both women and a transgenic mouse model. In this study, we generated a Notch gain-of-function transgenic mouse by conditionally overexpressing the Notch1 intracellular domain (N1ICD) in the reproductive tract driven by a progesterone receptor (Pgr) -Cre. We show that the overexpression of N1ICD in the uterus results in complete infertility as a consequence of multiple developmental and physiological defects, including the absence of uterine glands and dysregulation of progesterone and estrogen signaling by a Recombination Signal Binding Protein Jκ-dependent signaling mechanism. We further show that the inhibition of progesterone signaling is caused by hypermethylation of its receptor Pgr by Notch1 overexpression through the transcription factor PU.1 and DNA methyltransferase 3b (Dnmt3b). We have generated a mouse model to study the consequence of increased Notch signaling in female reproduction and provide the first evidence, to our knowledge, that Notch signaling can regulate epigenetic modification of the Pgr. mouse uterus | Notch1 | Pgr | methylation | infertility

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Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility

Strug

Jeong

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…While progesterone inhibits estrogen-induced epithelial proliferation, it cooperates with estrogen to promote stromal cell proliferation. Previous studies employing tissue recombination techniques and uterine conditional PR knockout mouse models have demonstrated that both stromal and epithelial PR are required to antagonize estrogen function in the epithelium (Franco et al, 2012, Kurita et al, 1998, Lydon et al, 1995. In mice lacking the PR co-chaperone, FKBP52, uterine receptivity is disrupted due to exaggerated estrogen activity, which resulted from reduced progesterone activity and failure of uterine epithelial differentiation (Tranguch et al, 2005b).…”

Section: Molecular Basis Of Uterine Receptivitymentioning

confidence: 99%

Molecular determinants of uterine receptivity

Tu¹,

Hao²,

Zhang³

et al. 2014

Int. J. Dev. Biol.

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Uterine receptivity is defined as a limited period when the uterine environment is conducive to blastocyst acceptance and implantation. Any disturbance of this early pregnancy event will compromise pregnancy success. In this review, we first briefly summarize uterine morphological coordination for the attainment of receptivity, then focus on elucidating the molecular complexity in establishing uterine receptivity and hence embryo implantation. A better understanding of the molecular basis governing uterine receptivity will help to improve the outcome of natural pregnancy and pregnancy conceived via assisted reproductive techniques.

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“…In their regulation of physiological events in the uterus, these sex steroid hormones act both cell autonomously and nonautonomously through their TF receptors (1,10). In either case they induce the expression of downstream TFs in the target cell that propagate the initial signal.…”

Section: Ishikawa Cell Proliferation Is Negatively Regulated By Klf15mentioning

confidence: 99%

“…Recent cell-specific gene targeting shows that E 2 induced epithelial cell proliferation is regulated through stromal localized ER (7) that causes the synthesis of paracrine factors, including IGF-1, that act on the epithelial cells (8). PR is required in the uterine epithelium and stroma and causes inhibition of E 2 -induced epithelial cell proliferation (9,10). Despite these cell-specific requirements for the receptor, each hormone induces a cascade of downstream effectors including transcription factors (TF) that propagate the hormonal signal (1).…”

mentioning

confidence: 99%

KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing

Ray

Pollard²

2012

Proc. Natl. Acad. Sci. U.S.A.

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In the epithelial compartment of the uterus, estradiol-17β (E 2 ) induces cell proliferation while progesterone (P 4 ) inhibits this response and causes differentiation of the cells. In this study, we identified the mechanism whereby E 2 and P 4 reciprocally regulate the expression of minichromosome maintenance (MCM)-2, a protein that is an essential component of the hexameric MCM-2 to 7 complex required for DNA synthesis initiation. We show in the uterine epithelium that Kruppel-like transcription (KLF) factors, KLF 4 and 15, are inversely expressed; most importantly, they bind to the Mcm2 promoter under the regulation of E 2 and P 4 E 2 , respectively. After P 4 E 2 exposure and in contrast to E 2 treated mice, the Mcm2 promoter displays increased histone 3 (H3) methylation and the recruitment of histone deacetylase 1 and 3 with the concomitant deacetylation of H3. This increased methylation and decreased acetylation is associated with an inhibition of RNA polymerase II binding, indicating an inactive Mcm2 promoter following P 4 E 2 treatment. Using transient transfection assays in the Ishikawa endometrial cell line, we demonstrate that Mcm2 promoter activity is hormonally stimulated by E 2 and that KLF15 inhibits this E 2 enhanced transcription. KLF15 expression also blocks Ishikawa cell proliferation through inhibition of MCM2 protein level. Importantly, in vivo expression of KLF15 in an estrogenized uterus mimics P 4 's action by inhibiting E 2 -induced uterine epithelial MCM-2 expression and DNA synthesis. KLF15 is therefore a downstream physiological mediator of progesterone's cell cycle inhibitory action in the uterine epithelium.endometrium | implantation | menstrual cycle | endometriosis E stradiol-17β (E 2 ) and progesterone (P 4 ) directs uterine preparation for pregnancy. These hormones synthesized cyclically in humans cause a sequential series of proliferative and differentiation events in the uterine stroma and epithelium that result in the epithelium being receptive to the blastocyst for attachment and subsequent implantation (1). Despite this close control of uterine cell proliferation, aberrant proliferative conditions of the human endometrium are common. For example, endometrial polyps and endometriosis are caused by inappropriate proliferation of the uterus, while unopposed estrogen stimulation is associated with menstrual irregularities and endometrial hyperplasia/adenocarcinoma (2). Endometrial cancer is the most common female genital tract malignancy and is responsible for 6% of cancer deaths of women in the United States and more worldwide (3). However, the molecular mechanisms underlying these pathologies are still obscure, as are the molecular mechanisms involved in normal hormonal regulation of cell proliferation in the endometrium, which is essential for successful pregnancy (4).The mouse uterus provides a unique in vivo model to study the regulation of epithelial cell proliferation as the physiological actions of E 2 and P 4 E 2 can be recapitulated in ovariectomized animals by treat...

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Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function

Cited by 137 publications

References 47 publications

Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility

Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility

Molecular determinants of uterine receptivity

KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing

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