Retinoid Signaling Controlled by SRC-2 in Decidualization Revealed by Transcriptomics

Szwarc, Maria M.; Long, Hai; Gibbons, William E.; White, Lisa D.; Mo, Qianxing; Kommagani, Ramakrishna; Lanz, Rainer B.; DeMayo, Francesco J.; O’Malley, Bert W.; Lydon, John P.

doi:10.1530/rep-18-0282

Cited by 12 publications

(17 citation statements)

References 47 publications

(64 reference statements)

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“…Microarray analysis further revealed that SRC-2 is necessary for P4 regulation of Wnt signaling, BMP2 signaling, and ESR1 signaling [110]. The requirement of SRC-2 for decidualization was also confirmed in in vitro decidualization of human endometrial stromal cells [115], and transcriptomic analysis revealed that 50% of SRC-2-regulated genes are also regulated by PGR [116], supporting the close relationship of these factors in transcriptional regulation of the decidualization process.…”

Section: Steroid Hormone Regulation Of Endometrial Functionmentioning

confidence: 95%

Progesterone and Estrogen Signaling in the Endometrium: What Goes Wrong in Endometriosis?

Marquardt

Kim

Shin

et al. 2019

IJMS

287

203

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In the healthy endometrium, progesterone and estrogen signaling coordinate in a tightly regulated, dynamic interplay to drive a normal menstrual cycle and promote an embryo-receptive state to allow implantation during the window of receptivity. It is well-established that progesterone and estrogen act primarily through their cognate receptors to set off cascades of signaling pathways and enact large-scale gene expression programs. In endometriosis, when endometrial tissue grows outside the uterine cavity, progesterone and estrogen signaling are disrupted, commonly resulting in progesterone resistance and estrogen dominance. This hormone imbalance leads to heightened inflammation and may also increase the pelvic pain of the disease and decrease endometrial receptivity to embryo implantation. This review focuses on the molecular mechanisms governing progesterone and estrogen signaling supporting endometrial function and how they become dysregulated in endometriosis. Understanding how these mechanisms contribute to the pelvic pain and infertility associated with endometriosis will open new avenues of targeted medical therapies to give relief to the millions of women suffering its effects.

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Section: Steroid Hormone Regulation Of Endometrial Functionmentioning

confidence: 95%

Progesterone and Estrogen Signaling in the Endometrium: What Goes Wrong in Endometriosis?

Marquardt

Kim

Shin

et al. 2019

IJMS

287

203

View full text Add to dashboard Cite

show abstract

“…As described above, stromal-derived SRC-2 has a clear modifier role in progesterone signaling processes in the endometrium that are for important embryo implantation; however, the involvement of endometrial epithelial SRC-2 in the implantation process is unknown; and finally (4) In addition to metabolic pathways, can SRC-2 control other progesterone responsive signals that are crucial for endometrial stromal cell decidualization? Recent transcriptomic and cistromic investigations have not only underscored the critical importance of SRC-2 in the full induction of the majority of known molecular mediators of progesterone during human endometrial stromal cell decidualization but have also uncovered new gene targets coregulated by SRC-2 and the PGR that may represent new lines of future investigation to understand coregulator control of early progesterone responses in the endometrium during the periimplantation period ( Szwarc et al, 2018a ).…”

Section: Modifiers Of Pgr Mediated Responses In the Endometrial Epithmentioning

confidence: 99%

Illuminating the “Black Box” of Progesterone-Dependent Embryo Implantation Using Engineered Mice

Maurya

DeMayo

Lydon

2021

Front. Cell Dev. Biol.

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Synchrony between progesterone-driven endometrial receptivity and the arrival of a euploid blastocyst is essential for embryo implantation, a prerequisite event in the establishment of a successful pregnancy. Advancement of embryo implantation within the uterus also requires stromal fibroblasts of the endometrium to transform into epithelioid decidual cells, a progesterone-dependent cellular transformation process termed decidualization. Although progesterone is indispensable for these cellular processes, the molecular underpinnings are not fully understood. Because human studies are restricted, much of our fundamental understanding of progesterone signaling in endometrial periimplantation biology comes from in vitro and in vivo experimental systems. In this review, we focus on the tremendous progress attained with the use of engineered mouse models together with high throughput genome-scale analysis in disclosing key signals, pathways and networks that are required for normal endometrial responses to progesterone during the periimplantation period. Many molecular mediators and modifiers of the progesterone response are implicated in cross talk signaling between epithelial and stromal cells of the endometrium, an intercellular communication system that is critical for the ordered spatiotemporal control of embryo invasion within the maternal compartment. Accordingly, derailment of these signaling systems is causally linked with infertility, early embryo miscarriage and gestational complications that symptomatically manifest later in pregnancy. Such aberrant progesterone molecular responses also contribute to endometrial pathologies such as endometriosis, endometrial hyperplasia and cancer. Therefore, our review makes the case that further identification and functional analysis of key molecular mediators and modifiers of the endometrial response to progesterone will not only provide much-needed molecular insight into the early endometrial cellular changes that promote pregnancy establishment but lend credible hope for the development of more effective mechanism-based molecular diagnostics and precision therapies in the clinical management of female infertility, subfertility and a subset of gynecological morbidities.

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“…Therefore, both SUSD2 and DLL1 may play a role in Notch signaling in the endometrium, which, importantly, is also a well-known inducer of transcription program switching in the EMT. Szwarc et al (50) revealed progesterone-mediated retinoid signaling was co-regulated by SRC-2, a Src family kinase which is also a known inducer of transcription program switching in the EMT, thereby highlighting another important parallel between these two processes. Moreover, Whitby et al (44) found Scribble expression was increased in secretory phase stromal cells, which is a key polarity determinant in epithelial cells as discussed above.…”

Section: Comparison Of Cytoskeleton Regulation Between Plasma Membranmentioning

confidence: 99%

Alterations in Epithelial Cell Polarity During Endometrial Receptivity: A Systematic Review

2020

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Background: Abnormal endometrial receptivity is one of the major causes of embryo implantation failure and infertility. The plasma membrane transformation (PMT) describes the collective morphological and molecular alterations occurring to the endometrial luminal epithelium across the mid-secretory phase of the menstrual cycle to facilitate implantation. Dysregulation of this process directly affects endometrial receptivity and implantation. Multiple parallels between these alterations to confer endometrial receptivity in women have been drawn to those seen during the epithelial-mesenchymal transition (EMT) in tumorigenesis. Understanding these similarities and differences will improve our knowledge of implantation biology, and may provide novel therapeutic targets to manage implantation failure. Methods: A systematic review was performed using the Medline (Ovid), Embase, and Web of Science databases without additional limits. The search terms used were "(plasma membrane* or cell membrane*) and transformation*" and "endometrium or endometrial." Research studies on the PMT or its regulation in women, discussing either the endometrial epithelium, decidualized stroma, or both, were eligible for inclusion. Results: A total of 198 articles were identified. Data were extracted from 15 studies that matched the inclusion criteria. Collectively, these included studies confirmed the alterations occurring to the endometrial luminal epithelium during the PMT are similar to those seen during the EMT. Such similarities included alterations to the actin cytoskeleton remodeling of adherens junctions, integrin expression and epithelial-stromal communication. These were also some differences between these processes, such as the regulation of tight junctions and mucins, which need to be further researched. Conclusions: This review raised the prospect of shared and distinct mechanisms existing in PMT and EMT. Further investigation into similarities between the PMT in the endometrium and the EMT in tumorigenesis may provide new mechanistic insights into PMT and new targets for the management of implantation failure and infertility.

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Retinoid Signaling Controlled by SRC-2 in Decidualization Revealed by Transcriptomics

Cited by 12 publications

References 47 publications

Progesterone and Estrogen Signaling in the Endometrium: What Goes Wrong in Endometriosis?

Progesterone and Estrogen Signaling in the Endometrium: What Goes Wrong in Endometriosis?

Illuminating the “Black Box” of Progesterone-Dependent Embryo Implantation Using Engineered Mice

Alterations in Epithelial Cell Polarity During Endometrial Receptivity: A Systematic Review

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