Possible roles of the cAMP-mediators EPAC and RAP1 in decidualization of rat uterus

Kusama, Kaoru; Yoshie, Mikihiro; Tamura, Kazuhiro; Daikoku, Takiko; Takarada, Tsutomu; Tachikawa, Eiichi

doi:10.1530/rep-13-0654

Cited by 24 publications

(23 citation statements)

References 32 publications

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“…Since COX2 is indispensable for normal implantation (Lim et al 1997), the fine tuning of COX2 expression by ENaC/CREB-dependent miRNAs may be necessary for successful implantation. Of note, CREB has been reported to be activated in decidua cells (Kawarabayashi et al 2012, Kusama et al 2014) and implicated in preimplantation embryo development (O'Neill et al 2012). This study has demonstrated, for the first time, a critical role of CREB in embryo implantation in vivo, as evidenced by the CREB knockdown-induced implantation failure observed in this study.…”

Section: Discussionsupporting

confidence: 62%

Regulation of miR-101/miR-199a-3p by the epithelial sodium channel during embryo implantation: involvement of CREB phosphorylation

Sun¹,

Ruan²,

Guo³

et al. 2014

Reproduction

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In our previous study, we have demonstrated that the epithelial sodium channel (ENaC) mediates the embryo-derived signals leading to the activation of CREB and upregulation of cyclooxygenase type 2 (COX2) required for embryo implantation. This study aims to investigate whether microRNAs (miRNAs) are involved in the ENaC-induced upregulation of COX2 during embryo implantation. The results show that the levels of miR-101 and miR-199a-3p, two COX2 targeting miRNAs, are reduced by ENaC activation, and increased by ENaC inhibition or knock-down of ENaC subunit (ENaCa) in human endometrial surface epithelial (HES) cells or in mouse uteri during implantation. Phosphorylation of CREB is induced by the activation of ENaC, and blocked by ENaC inhibition or knockdown in HES cells. Knockdown of ENaCa or CREB in HES cells or in mouse uterus in vivo results in increases in miR-101 and miR-199a-3p, accompanied with decreases in COX2 protein levels and reduction in implantation rate. The downregulation of COX2 caused by knockdown of ENaC or CREB can be recovered by the inhibitors of miR-101 or miR-199a-3p in HES cells. These results reveal a novel molecular mechanism modulating COX2 expression during embryo implantation via ENaC-dependent CREB activation and COX2-targeting miRNAs.

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Section: Discussionsupporting

confidence: 62%

Regulation of miR-101/miR-199a-3p by the epithelial sodium channel during embryo implantation: involvement of CREB phosphorylation

Sun¹,

Ruan²,

Guo³

et al. 2014

Reproduction

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“…Interestingly, genes of significantly changed CpG methylation in the transition between age 18 and pregnancy belong to 5 signaling pathways which control various processes such as cell adhesion and cell division that are crucial events occurring in the trophoblast and uterus (Rap1 signaling pathway, MAPK signaling pathway, Ras signaling pathway, calcium signaling pathway, and Hippo signaling pathway; Supplemental Table 2). 24 – 27 In addition, the “Endocytosis” pathway seems also to be linked to pregnancy indicating a survival phenomenon in response to environmental stressors in the placenta. 28 We likewise assume that the identification of 2 cancer pathways in this transition is due to a misclassification because tumorigenesis and pregnancy share characteristics of cell survival, cell proliferation, and cell migration.…”

Section: Discussionmentioning

confidence: 99%

Consistency and Variability of DNA Methylation in Women During Puberty, Young Adulthood, and Pregnancy

et al. 2017

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Prior DNA methylation (DNA-m) analyses have identified cytosine-phosphate-guanine (CpG) sites, which show either a significant change or consistency during lifetime. However, the proportion of CpGs that are neither significantly different nor consistent over time (indifferent CpGs) is unknown. We investigated the methylation dynamics, both longitudinal changes and consistency, in women from preadolescence to late pregnancy using DNA-m of peripheral blood cells. Consistency of cell type–adjusted DNA-m between paired individuals was assessed by regressing CpGs of subsequent age on the prior, stability by intraclass correlation coefficients (>0.5), and changes by linear mixed models. In the first 2 transitions (10-18 years and 18 years to early pregnancy), 19.5% and 20.9% CpGs were consistent, but only 0.35% in the third transition (from early to late pregnancy). Significant changes in methylation were found in 0.7%, 5.6%, and 0% CpGs, respectively. Functional enrichment analyses of genes with significant changes in DNA-m in early pregnancy (5.6%) showed that the maternal DNA-m seems to reflect signaling pathways between the uterus and the trophoblast. The transition from early to late pregnancy showed low consistency/stability and no changes, suggesting the presence of a large proportion of indifferent CpGs in late pregnancy.

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“…In several species, it has been recognized that the synchrony between the needs of developing embryos and the secretions of the uterus are critical for implantation and to maintain a successful pregnancy (Pope 1988, Bourdiec & Akoum 2014. Following embryo implantation, one of the critical steps to establish pregnancy in rodents and humans is the optimal decidualization of endometrial stromal cells (ESCs) (Kusama et al 2014). This step is intricately regulated by E 2 and P, which activate the transcription of target genes through the binding of their cognate receptors (Wetendorf & DeMayo 2012).…”

Section: Discussionmentioning

confidence: 99%

Effects of neonatal exposure to a glyphosate-based herbicide on female rat reproduction

Ingaramo¹,

Varayoud²,

Milesi³

et al. 2016

Reproduction

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In this study, we investigated whether neonatal exposure to a glyphosate-based herbicide (GBH) alters the reproductive performance and the molecular mechanisms involved in the decidualization process in adult rats. Newborn female rats received vehicle or 2 mg/kg/day of a GBH on postnatal days (PND) 1, 3, 5 and 7. On PND90, the rats were mated to evaluate (i) the reproductive performance on gestational day (GD) 19 and (ii) the ovarian steroid levels, uterine morphology, endometrial cell proliferation, apoptosis and cell cycle regulators, and endocrine pathways that regulate uterine decidualization (steroid receptors/COUP-TFII/Bmp2/Hoxa10) at the implantation sites (IS) on GD9. The GBH-exposed group showed a significant increase in the number of resorption sites on GD19, associated with an altered decidualization response. In fact, on GD9, the GBH-treated rats showed morphological changes at the IS, associated with a decreased expression of estrogen and progesterone receptors, a downregulation of COUP-TFII (Nr2f2) and Bmp2 mRNA and an increased expression of HOXA10 and the proliferation marker Ki67(Mki67) at the IS. We concluded that alterations in endometrial decidualization might be the mechanism of GBH-induced post-implantation embryo loss.

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Possible roles of the cAMP-mediators EPAC and RAP1 in decidualization of rat uterus

Cited by 24 publications

References 32 publications

Regulation of miR-101/miR-199a-3p by the epithelial sodium channel during embryo implantation: involvement of CREB phosphorylation

Regulation of miR-101/miR-199a-3p by the epithelial sodium channel during embryo implantation: involvement of CREB phosphorylation

Consistency and Variability of DNA Methylation in Women During Puberty, Young Adulthood, and Pregnancy

Effects of neonatal exposure to a glyphosate-based herbicide on female rat reproduction

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