Roles of Estrogen Receptor-α and the Coactivator MED1 During Human Endometrial Decidualization

Abstract The steroid hormones 17β-estradiol and progesterone are critical regulators of endometrial stromal cell differentiation, known as decidualization, which is a prerequisite for successful establishment of pregnancy. The present study using primary human endometrial stromal cells (HESCs) addressed the role of estrogen receptor-α (ESR1) in decidualization. Knockdown of ESR1 transcripts by RNA interference led to a marked reduction in decidualization of HESCs. Gene expression profiling at an early stage of decidualization indicated that ESR1 negatively regulates several cell cycle regulatory factors, thereby suppressing the proliferation of HESCs as these cells enter the differentiation program. ESR1 also controls the expression of WNT4, FOXO1, and progesterone receptor (PGR), well-known mediators of decidualization. Whereas ESR1 knockdown strongly inhibited the expression of FOXO1 and WNT4 transcripts within 24 hours of the initiation of decidualization, PGR expression remained unaffected at this early time point. Our study also revealed a major role of cAMP signaling in influencing the function of ESR1 during decidualization. Using a proteomic approach, we discovered that the cAMP-dependent protein kinase A (PKA) phosphorylates Mediator 1 (MED1), a subunit of the mediator coactivator complex, during HESC differentiation. Using immunoprecipitation, we demonstrated that PKA-phosphorylated MED1 interacts with ESR1. The PKA-dependent phosphorylation of MED1 was also correlated with its enhanced recruitment to estrogen-responsive elements in the WNT4 gene. Knockdown of MED1 transcripts impaired the expression of ESR1-induced WNT4 and FOXO1 transcripts and blocked decidualization. Based on these findings, we conclude that modulation of ESR1-MED1 interactions by cAMP signaling plays a critical role in human decidualization.

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Uterine Epithelial Estrogen Receptor-α Controls Decidualization via a Paracrine Mechanism

Molecular Endocrinology ◽

10.1210/me.2015-1142 ◽

2015 ◽

Vol 29 (9) ◽

pp. 1362-1374 ◽

Cited By ~ 38

Author(s):

S. Pawar ◽

M. J. Laws ◽

I. C. Bagchi ◽

M. K. Bagchi

Keyword(s):

Estrogen Receptor ◽

Transcription Factor ◽

Embryo Implantation ◽

Critical Role ◽

Estrogen Receptor Α ◽

Signal Transducer ◽

Factor Ii ◽

Cell Type Specific ◽

Transcription 3

Abstract Steroid hormone-regulated differentiation of uterine stromal cells, known as decidualization, is essential for embryo implantation. The role of the estrogen receptor-α (ESR1) during this differentiation process is unclear. Development of conditional Esr1-null mice showed that deletion of this gene in both epithelial and stromal compartments of the uterus leads to a complete blockade of decidualization, indicating a critical role of ESR1 during this process. To further elucidate the cell type-specific function of ESR1 in the uterus, we created WEd/d mice in which Esr1 is ablated in uterine luminal and glandular epithelia but is retained in the stroma. Uteri of WEd/d mice failed to undergo decidualization, indicating that epithelial ESR1 contributes to stromal differentiation via a paracrine mechanism. We noted markedly reduced production of the leukemia inhibitory factor (LIF) in WEd/d uteri. Supplementation with LIF restored decidualization in WEd/d mice. Our study indicated that LIF acts synergistically with progesterone to induce the expression of Indian hedgehog (IHH) in uterine epithelium and its receptor patched homolog 1 in the stroma. IHH then induces the expression of chicken ovalbumin upstream promoter-transcription factor II, a transcription factor that promotes stromal differentiation. To address the mechanism by which LIF induces IHH expression, we used mice lacking uterine epithelial signal transducer and activator of transcription 3, a well-known mediator of LIF signaling. Our study revealed that LIF-mediated induction of IHH occurs without the activation of epithelial signal transducer and activator of transcription 3 but uses an alternate pathway involving the activation of the ERK1/2 kinase. Collectively our results provide unique insights into the paracrine mechanisms by which ESR1 directs epithelial-stromal dialogue during pregnancy establishment.

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Estrogen-Dependent and -Independent Estrogen Receptor-α Signaling Separately Regulate Male Fertility

Endocrinology ◽

10.1210/en.2008-1016 ◽

2009 ◽

Vol 150 (6) ◽

pp. 2898-2905 ◽

Cited By ~ 46

Author(s):

Kerstin W. Sinkevicius ◽

Muriel Laine ◽

Tamara L. Lotan ◽

Karolina Woloszyn ◽

John H. Richburg ◽

...

Keyword(s):

Estrogen Receptor ◽

Male Fertility ◽

Reproductive Tract ◽

Cell Function ◽

Critical Role ◽

Estrogen Receptor Α ◽

Male Reproductive Tract ◽

Efferent Ductule

Estrogen receptor-α (ERα) plays a critical role in male reproductive tract development and fertility. To determine whether estrogen-dependent and -independent ERα mechanisms are involved in male fertility, we examined male estrogen nonresponsive ERα knock-in mice. These animals have a point mutation (G525L) in the ligand-binding domain of ERα that significantly reduces interaction with, and response to, endogenous estrogens but does not affect growth factor activation of ligand-independent ERα pathways. Surprisingly, we found that ligand-independent ERα signaling is essential for concentrating epididymal sperm via regulation of efferent ductule fluid reabsorption. In contrast, estrogen-dependent ERα signaling is required for germ cell viability, most likely through support of Sertoli cell function. By treating estrogen nonresponsive ERα knock-in (ENERKI) mice with the ERα selective synthetic agonist propyl pyrazole triol, which is able to bind and activate G525L ERα in vivo, we discovered male fertility required neonatal estrogen-mediated ERα signaling. Thus, our work indicates both estrogen-dependent and -independent pathways play separable roles in male murine reproductive tract development and that the role of ERα in human infertility should be examined more closely.

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Membrane estrogen receptor α is essential for estrogen signaling in the male skeleton

Journal of Endocrinology ◽

10.1530/joe-18-0406 ◽

2018 ◽

Vol 239 (3) ◽

pp. 303-312 ◽

Cited By ~ 2

Author(s):

H H Farman ◽

K L Gustafsson ◽

P Henning ◽

L Grahnemo ◽

V Lionikaite ◽

...

Keyword(s):

Estrogen Receptor ◽

Estrogen Receptor Α ◽

Estrogen Signaling ◽

Areal Bone Mineral Density ◽

Male Mice ◽

Mineral Density ◽

Intact Male ◽

Trabecular Thickness ◽

Total Body

The importance of estrogen receptor α (ERα) for the regulation of bone mass in males is well established. ERα mediates estrogenic effects both via nuclear and membrane-initiated ERα (mERα) signaling. The role of mERα signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERα signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ERα to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (µCT) analysis of tibia in 3-month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mERα is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis.

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Critical Role of PDE4D in β2-Adrenoceptor-dependent cAMP Signaling in Mouse Embryonic Fibroblasts

Journal of Biological Chemistry ◽

10.1074/jbc.m803306200 ◽

2008 ◽

Vol 283 (33) ◽

pp. 22430-22442 ◽

Cited By ~ 36

Author(s):

Matthew D. Bruss ◽

Wito Richter ◽

Kathleen Horner ◽

S.-L. Catherine Jin ◽

Marco Conti

Keyword(s):

Critical Role ◽

Camp Signaling ◽

Mouse Embryonic Fibroblasts ◽

Embryonic Fibroblasts

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The role of activation functions 1 and 2 of estrogen receptor‐α for the effects of estradiol and selective estrogen receptor modulators in male mice

Journal of Bone and Mineral Research ◽

10.1002/jbmr.1842 ◽

2013 ◽

Vol 28 (5) ◽

pp. 1117-1126 ◽

Cited By ~ 18

Author(s):

Anna E Börjesson ◽

Helen H Farman ◽

Cecilia Engdahl ◽

Antti Koskela ◽

Klara Sjögren ◽

...

Keyword(s):

Estrogen Receptor ◽

Selective Estrogen Receptor Modulators ◽

Estrogen Receptor Α ◽

Activation Functions ◽

Male Mice ◽

Estrogen Receptor Modulators ◽

Receptor Modulators

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Expression of Estrogen Receptor Alpha and Evaluation of Histological Degeneration Scores in Fibroblasts of Hypertrophied Ligamentum Flavum: A Qualitative Study

Biomolecules ◽

10.3390/biom11121752 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1752

Author(s):

Christina C. Westhoff ◽

Christian-Dominik Peterlein ◽

Hanna Daniel ◽

Juergen R. Paletta ◽

Roland Moll ◽

...

Keyword(s):

Estrogen Receptor ◽

Estrogen Receptor Alpha ◽

Ligamentum Flavum ◽

Estrogen Receptor Α ◽

Group Differences ◽

Elastic Fibers ◽

Disk Herniation ◽

Spinal Decompression ◽

Lumbar Spinal

The most common spinal disorder in elderly is lumbar spinal stenosis (LSS), resulting partly from ligamentum flavum (LF) hypertrophy. Its pathophysiology is not completely understood. The present study wants to elucidate the role of estrogen receptor α (ER α) in fibroblasts of hypertrophied LF. LF samples of 38 patients with LSS were obtained during spinal decompression. Twelve LF samples from patients with disk herniation served as controls. Hematoxylin & Eosin (H&E) and Elastica stains and immunohistochemistry for ER α were performed. The proportions of fibrosis, loss and/or degeneration of elastic fibers and proliferation of collagen fibers were assessed according to the scores of Sairyo and Okuda. Group differences in the ER α and Sairyo and Okuda scores between patients and controls, male and female sex and absence and presence of additional orthopedic diagnoses were assessed with the Mann–Whitney U test. There was a tendency towards higher expression of ER α in LF fibroblasts in the hypertrophy group (p = 0.065). The Sairyo and Okuda scores were more severe for the hypertrophy group but, in general, not statistically relevant. There was no statistically relevant correlation between the expression of ER α and sex (p = 0.326). ER α expression was higher in patients with osteochondrosis but not statistically significant (p = 0.113). In patients with scoliosis, ER α expression was significantly lower (p = 0.044). LF hypertrophy may be accompanied by a higher expression of ER α in fibroblasts. No difference in ER α expression was observed regarding sex. Further studies are needed to clarify the biological and clinical significance of these findings.

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