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  • PGR regulation of epithelium stroma crosstalk is proven

    2024-05-24

    PGR regulation of epithelium–stroma crosstalk is proven by numerous studies that utilize genetically engineered mouse models. Before embryo implantation, epithelial PGR mediates the progesterone signal to transcriptionally increase the Ihh levels 13, 15. Epithelial IHH then activates the stromal hedgehog pathway to promote expression of the downstream effector COUP-TFII (also known as NR2F2) [16]. In stromal cells, COUP-TFII suppresses estrogen signaling and ceases epithelial proliferation, likely through the HAND2 mediated reduction of the FGF-ERK pathway 17, 18, 19, 20, 21. While COUP-TFII directly promotes stromal PGR expression and progesterone increases stromal HAND2 levels 17, 20, 22, it is not clear whether COUP-TFII regulates HAND2 directly or through biotin-LC-LC-tyramide stromal PGR. Physiologically, this epithelial PGR-initiated intercompartmental crosstalk shifts the epithelial biotin-LC-LC-tyramide from a proliferative to a differentiated state, ready for subsequent embryo implantation (Figure 1). The epithelial PGR-IHH pathway also primes the stroma for decidualization through COUP-TFII and in conjunction with stromal EGFR signaling (Figure 2). Mouse and ex vivo cultured human endometrial stromal cell (HESC) studies reveal that stromal COUP-TFII promotes Wnt4 expression to simulate decidualization 17, 22, 23, 24. Results from uterine COUP-TFII deficient mice further indicate a positive regulatory role of COUP-TFII on Bmp2 expression [17]. Wnt4 has also been shown downstream of BMP2 and is positively regulated by PGR and FOXO1 23, 25. Signals transduced by the stromal EGFR converge with the PGR-IHH axis at Bmp2 and Wnt4, as evidenced by the impaired decidualization in uterine-specific Egfr knockout mice and in EGFR knockdown HESCs [26]. EGFR also phosphorylates WNK1 [26] and WNK1 phosphorylation has been shown to be essential for WNK1-mediated signal transduction [27]. WNK1’s function in HESCs was further revealed by a knockdown experiment in which reduced WNK1 levels impaired HESC decidualization 26, 28. Downstream further, emerging evidence suggests that the well-known WNK1-MAPK7 axis acts downstream of the EGFR pathway for stromal decidualization. However, the observation that MAPK7 knockdown affects just a subset of decidualization marker genes renders the role of MAPK7 in stromal differentiation unclear [28].
    Progesterone Signaling Modifiers for Endometrial Homeostasis at Early Pregnancy
    Maintaining Normal Endometrial Epithelia by Progesterone Signaling Modifiers Aberrant differentiation of stratified squamous endometrial epithelium is seen in long-term disruption of progesterone signaling via progesterone antagonists [41]. Endometrial squamous cell metaplasia is also observed in mutants that exhibit altered progesterone signaling, including Wnt4, Ctnnb1, and Gata2 conditional knockout mice, under estrogen challenges 24, 29, 42. Expression of TP63, a homolog of the p53 transcription factor for epithelial stemness and a known driver of epithelial stratification, precedes the development of metaplasia and persists in the squamous cells 24, 29, 42, 43, 44. Moreover, ectopic TP63 expressing cells were also observed in endometrium of Fzd1-null [45] and constitutively active SMO overexpression mice [46]. These observations highlight the pivotal role of unperturbed endometrial progesterone signaling in maintaining uterine epithelial homeostasis. Notably, TP63 protein is often found in human endometrial polyps and metaplastic epithelia 47, 48, and endometrial polyps are associated with aberrant menstrual bleeding and infertility, with rare occasions of malignancy. Disrupted progesterone signaling results in an increased number of TP63-expressing cells; this has implications for a potential mechanism for the development of endometrial polyps.
    PGR Isoforms in Regulation of Myometrial Physiological States
    Concluding Remarks and Future Perspectives The PGR is a versatile signal transducer that can command distinct genomic and nongenomic programs to meet the demand of various physiological conditions. Such functional plasticity is achieved by a combination of modulators on PGR levels and activities, including ligand accessibility, isoform composition, transcription and post-transcriptional modifications, subcellular distribution, and interaction with coregulators. While the known pathways and progesterone signaling modifiers reviewed here and by others have illuminated the complexity of this regulatory network 8, 73, 74, 75, the recent discovery of GATAD2B as a novel progesterone interacting protein and the detailed investigation of subcellular distribution of known PGR interacting transcription factor, AP-1, highlight the importance of further expanding our knowledge on the scope of the PGR signaling network 65, 76. New technologies, such as immunoprecipitation/chromatin immunoprecipitation, followed by mass spectrometry, have helped to identify novel interacting partners of hormone nuclear receptors 65, 77. Analyzing enriched motifs of DNA-binding proteins in the PGR occupying intervals, obtained through the chromatin immunoprecipitation (ChIP-seq) assay, can also identify candidate transcription regulators that coregulate gene expression with PGR 29, 34, 78. Given that PGR partners with different transcription regulators in a context dependent manner, aforementioned unbiased approaches would facilitate the decoding of key sets of factors, DNA-binding dependent or independent, that are required to work with PGR for specific genomic programs in the uterus.