Characterisation of Osteopontin in an In Vitro Model of Embryo Implantation

Berneau, Stéphane; Ruane, Peter T; Brison, Daniel R.; Kimber, Susan J.; Westwood, Melissa; Aplin, John D.

doi:10.3390/cells8050432

Cited by 25 publications

(15 citation statements)

References 57 publications

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“…To increase O-GlcNAcylated protein levels, mouse blastocysts were treated with the OGA inhibitor thiamet g (TMG) at 5 µM [ 33 , 34 , 35 ] during the E4.5–5.5 period when embryos are sensitive to signals that activate invasive implantation [ 10 , 36 , 37 ]. Untreated mouse blastocysts exhibited O-GlcNAcylated protein staining in the nucleus and especially the nuclear membrane ( Figure 1 A).…”

Section: Resultsmentioning

confidence: 99%

“…Here, TMG treatment during E4.5–5.5 also activated the embryos, suggesting that TMG-induced O-GlcNAcylation mimicked a stress response to promote breaching of the epithelium. E5.5 embryos activated by epithelial contact exhibit reduced expression of TE transcription factors Cdx2 , Gata2 and Gata3 and increased expression of the TGC transcription factor Hand1 , suggesting that activated TE initiates differentiation to TGC [ 36 , 37 ]. This pattern of downregulated TE transcription factors was observed at the transcript level in TMG-treated blastocysts and at the protein level for CDX2 and GATA3; however, Hand1 transcript levels were not changed by TMG.…”

Section: Discussionmentioning

confidence: 99%

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Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation

Ruane

Tan

Adlam

et al. 2020

Cells

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Embryo implantation begins with blastocyst trophectoderm (TE) attachment to the endometrial epithelium, followed by the breaching of this barrier by TE-derived trophoblast. Dynamic protein modification with O-linked β-N-acetylglucosamine (O-GlcNAcylation) is mediated by O-GlcNAc transferase and O-GlcNAcase (OGA), and couples cellular metabolism to stress adaptation. O-GlcNAcylation is essential for blastocyst formation, but whether there is a role for this system at implantation remains unexplored. Here, we used OGA inhibitor thiamet g (TMG) to induce raised levels of O-GlcNAcylation in mouse blastocysts and human trophoblast cells. In an in vitro embryo implantation model, TMG promoted mouse blastocyst breaching of the endometrial epithelium. TMG reduced expression of TE transcription factors Cdx2, Gata2 and Gata3, suggesting that O-GlcNAcylation stimulated TE differentiation to invasive trophoblast. TMG upregulated transcription factors OVOL1 and GCM1, and cell fusion gene ERVFRD1, in a cell line model of syncytiotrophoblast differentiation from human TE at implantation. Therefore O-GlcNAcylation is a conserved pathway capable of driving trophoblast differentiation. TE and trophoblast are sensitive to physical, chemical and nutritive stress, which can occur as a consequence of maternal pathophysiology or during assisted reproduction, and may lead to adverse neonatal outcomes and associated adult health risks. Further investigation of how O-GlcNAcylation regulates trophoblast populations arising at implantation is required to understand how peri-implantation stress affects reproductive outcomes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation

Ruane

Tan

Adlam

et al. 2020

Cells

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“…Osteopontin (OPN) is a glycosylated phosphoprotein expressed in the endometrial epithelium and implicated in adhesion and signaling roles at the embryo-epithelium interface [68,69]. OPN is also a bone associated protein, produced by several bone cell types (osteoblasts and osteoclasts) and extra-osseous tissue (skin, kidney and lung).…”

Section: Uterusmentioning

confidence: 99%

Mother and Embryo Cross-Communication

Idelevich¹,

Vilella

2020

Genes

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Endometrial receptivity is a biosensor for embryo quality, as embryos with reduced developmental potential are rejected. However, embryo quality only accounts for an estimated one-third of implantation failures, with suboptimal endometrial receptivity accounting for the remaining two-thirds. As pregnancy progresses, a uterus continues to engage in close communication with an embryo/fetus, exchanging information in the form of endocrine, paracrine, and other cues. Given the long mammalian gestation period, this dialogue is intricate, diverse, and, currently, not fully understood. Recent progress and the availability of high-throughput techniques, including transcriptomics, proteomics, and metabolomics, has allowed the simultaneous examination of multiple molecular changes, enhancing our knowledge in this area. This review covers the known mechanisms of mother–embryo cross-communication gathered from animal and human studies.

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“…During this process, estrogen (E) and progesterone (P) secreted by the ovaries play an important role, which promote the transformation of endometrium toward secretory and receptive condition in order to receive the embryo (Lim & Wang 2010). At the same time, many molecules, including leukemia inhibitory factor (LIF), integrin αvβ3, and osteopontin (OPN), were released by EECs to enhance the endometrial receptivity (Schmitz et al 2014, Zheng et al 2016, Berneau et al 2019. Therefore, the EEC-mediated endometrial receptivity plays a critical role in embryo implantation, whose mechanisms have been largely unknown.…”

Section: Introductionmentioning

confidence: 99%

miR-23a-3p increases endometrial receptivity via CUL3 during embryo implantation

Huang

Chen

Fan

et al. 2020

Journal of Molecular Endocrinology

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A receptive endometrium is required in a successful embryo implantation. The ubiquitination-induced β-catenin degradation is related to the implantation failure.This study aimed to elucidate whether miR-23a-3p regulates endometrial receptivity via the modulation of β-catenin ubiquitination.The expressions of miR-23a-3p and CUL3 were detected in endometrial epithelial cells (EECs) isolated from pregnant mice and in hormone-induced EEC-like Ishikawa cells. The ubiquitination experiment was performed to explore the effect of CUL3 and miR-23a-3p on β-catenin ubiquitination level. The trophoblast attachment was detected by co-culturing JAR (choriocarcinoma cell line) spheroids with Ishikawa cell monolayers. miR-23a-3p was upregulated while CUL3 was downregulated in EECs at day 4 after pregnancy compared with day 1, as well as in hormone-induced Ishikawa cells. miR-23a-3p positively regulated the protein level of β-catenin without affecting the mRNA level. The ubiquitination and degradation of β-catenin was suppressed by miR-23a-3p while it was promoted by CUL3. Immunoprecipitation confirmed the binding between CUL3 and β-catenin. Luciferase reporter assay confirmed the target relationship between miR-23a-3p and CUL3. The ubiquitination of β-catenin was modulated by the miR-23a-3p/CUL3 pathway. The overexpression of miR-23a-3p promoted JAR spheroid attachments in Ishikawa cells.miR-23a-3p is beneficial for the endometrial receptivity and embryo implantation, whose mechanism is partly through the modulation of CUL3/β-catenin.

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Characterisation of Osteopontin in an In Vitro Model of Embryo Implantation

Cited by 25 publications

References 57 publications

Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation

Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation

Mother and Embryo Cross-Communication

miR-23a-3p increases endometrial receptivity via CUL3 during embryo implantation

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