Coordinated Regulation Among Progesterone, Prostaglandins, and EGF-Like Factors in Human Ovulatory Follicles

Choi, Yohan; Wilson, Kalin; Hannon, Patrick R.; Rosewell, Katherine L.; Brännström, Mats; Akin, James W.; Curry, Thomas E.; Jo, Misung

doi:10.1210/jc.2016-3153

Cited by 47 publications

(47 citation statements)

References 40 publications

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“…A total of 60 gene sets were enriched in upregulated genes and 223 gene sets were enriched in downregulated genes at FDR q-value < 0.05. The size of the node corresponds to the number of genes in each gene set enhance PTGS2 (also upregulated in our MII-CC cohort) via EGF to increase prostaglandin production and maintenance of chromosomal spindles [33,[54][55][56]. In addition, AREG mediates hCG-induced STAR expression (also upregulated in our MII-CC cohort), which plays a key role in steroid and progesterone production in human granulosa cells [57], and is a potential predictive biomarker for nuclear maturation [58] and oocyte quality [33].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomics of cumulus cells – a window into oocyte maturation in humans

et al. 2020

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Background: Cumulus cells (CC) encapsulate growing oocytes and support their growth and development. Transcriptomic signatures of CC have the potential to serve as valuable non-invasive biomarkers for oocyte competency and potential. The present sibling cumulus-oocyte-complex (COC) cohort study aimed at defining functional variations between oocytes of different maturity exposed to the same stimulation conditions, by assessing the transcriptomic signatures of their corresponding CC. CC were collected from 18 patients with both germinal vesicle and metaphase II oocytes from the same cycle to keep the biological variability between samples to a minimum. RNA sequencing, differential expression, pathway analysis, and leading-edge were performed to highlight functional differences between CC encapsulating oocytes of different maturity. Results: Transcriptomic signatures representing CC encapsulating oocytes of different maturity clustered separately on principal component analysis with 1818 genes differentially expressed. CCs encapsulating mature oocytes were more transcriptionally synchronized when compared with CCs encapsulating immature oocytes. Moreover, the transcriptional activity was lower, albeit not absent, in CC encapsulating mature oocytes, with 2407 fewer transcripts detected than in CC encapsulating immature (germinal vesicle-GV) oocytes. Hallmark pathways and ovarian processes that were affected by oocyte maturity included cell cycle regulation, steroid metabolism, apoptosis, extracellular matrix remodeling, and inflammation. Conclusions: Herein we review our findings and discuss how they align with previous literature addressing transcriptomic signatures of oocyte maturation. Our findings support the available literature and enhance it with several genes and pathways, which have not been previously implicated in promoting human oocyte maturation. This study lays the ground for future functional studies that can enhance our understanding of human oocyte maturation.

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Section: Discussionmentioning

confidence: 99%

Transcriptomics of cumulus cells – a window into oocyte maturation in humans

et al. 2020

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“…The hCG-and PGRdependent organic anion transporter, Slco2a1, contributes to prostaglandin synthesis and action in granulosa cells of ovulatory follicles in humans. 49,50 The zinc transporter, Slc39a14, is expressed in cumulus granulosa cells (CGCs) and is thought to regulate free intracellular zinc in mouse oocytes. 51 Direct analysis of the amino acid transporter, Slc7a11, has primarily been limited to regulation of intracellular glutathione synthesis in neuronal tissue, but could play a similar role in FSH-and LH-dependent glutathione production in granulosa cells to support oocyte health.…”

Section: Ir-cko Mice Demonstrate Misregulation Of Gene Involved In mentioning

confidence: 99%

Periovulatory insulin signaling is essential for ovulation, granulosa cell differentiation, and female fertility

et al. 2019

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Recent studies have demonstrated an essential role for insulin signaling in folliculogenesis as conditional ablation of Igf1r in primary follicles elicits defective follicle-stimulating hormone responsiveness blocking development at the preantral stage. Thus the potential role of insulin action in the periovulatory window and in the corpus luteum is unknown. To examine this, we generated conditional Insr, Igf1r, and double receptor knockout mice driven by Pgr-Cre. These models escape the preantral follicle block and in response to superovulatory gonadotropins exhibit normal distribution of ovarian follicles and corpora lutea. However, single ablation of Igf1r leads to subfertility and mice lacking both receptors are infertile. Double knockout mice have impaired oocyte development and ovulation. While some oocytes are released and fertilized, subsequent embryo development is retarded, and the embryos potentially fail to thrive due to lack of luteal support. In support of this, we found reduced expression of key enzymes in the steroid synthesis pathway and reduced serum progesterone. In addition to metabolic and steroidogenic pathways, RNA-sequencing analysis revealed transcription factor-3 as an important transcription factor downstream of insulin signaling. Collectively, these results highlight the importance of growth factors of the insulin family during two distinct windows of follicular development, ovulation, and luteinization. K E Y W O R D Sfemale reproduction, insulin signaling, knockout mouse, ovary | 2377 SEKULOVSKI Et aL. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section.How to cite this article: Sekulovski N, Whorton AE, Shi M, Hayashi K, MacLean JA II. Periovulatory insulin signaling is essential for ovulation, granulosa cell differentiation, and female fertility. The FASEB

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“…Previously, we identified the key role of ATF4 in modulating the expression of COX2 in hGCs (Figure 2B ). Consistently, hCG could also induce COX2 expression ( 18 , 19 ). The increases in COX2 and PGE2 levels are representative indicators of ovulation ( 36 , 37 ).…”

Section: Discussionmentioning

confidence: 59%

“…Cyclooxygenase-2 (COX2) is the key enzyme responsible for the conversion of arachidonic acid into prostaglandins, among which prostaglandin E2 (PGE2) plays important role in multiple physiological and pathological events. hCG can induce COX2 expression and PGE2 production ( 18 , 19 ). It was reported that COX2-deficient mice were susceptible to reproductive malfunction, such as ovulation disorder, decreased fertilization rate, and embryo implantation dysfunction.…”

Section: Introductionmentioning

confidence: 99%

ATF4 Contributes to Ovulation via Regulating COX2/PGE2 Expression: A Potential Role of ATF4 in PCOS

Liu

et al. 2018

Front. Endocrinol.

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Ovulatory disorder is common in patients with hyperprolactinemia or polycystic ovary syndrome (PCOS). Previous studies have shown that ATF4 plays critical role in apoptosis and glucose homeostasis, but its role in regulating reproductive function was not explored. The present study investigated the role of ATF4 in ovarian ovulatory function. Human granulosa cells (hGCs) from 48 women newly diagnosed with PCOS and 37 controls were used to determine ATF4 expression. In vitro cultured hGCs were used to detect the upstream and downstream genes of ATF4. A shRNA- Atf4 lentiviral vector (shAtf4) was injected into rat ovaries to establish an in vivo gene knockdown model to further assess the in vivo relevance of the results from PCOS women. We found that ATF4 expression was lower in hGCs from PCOS patients than in hGCs from non-PCOS women. Many pivotal transcripts involved in cumulus-oocyte complex (COC) expansion, extracellular matrix (ECM) remodeling, and progesterone production were significantly down-regulated after ATF4 knockdown. ChIP-qPCR assays indicated that ATF4 could directly bind to the COX2 promoter and that ATF4 knockdown could attenuate human chorionic gonadotropin (hCG)-induced COX2 expression and PGE2 production. The in vivo study showed that shRNA-lentivirus mediated Atf4 knockdown in rat ovaries led to reduced number of retrieved oocytes. Collectively, these findings suggested previously unknown roles of ATF4 in ovulation. Furthermore, ATF4 malfunction in PCOS patients may impact the ovulation process, which could contribute, in part, to the pathogenesis of PCOS.

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Coordinated Regulation Among Progesterone, Prostaglandins, and EGF-Like Factors in Human Ovulatory Follicles

Cited by 47 publications

References 40 publications

Transcriptomics of cumulus cells – a window into oocyte maturation in humans

Transcriptomics of cumulus cells – a window into oocyte maturation in humans

Periovulatory insulin signaling is essential for ovulation, granulosa cell differentiation, and female fertility

ATF4 Contributes to Ovulation via Regulating COX2/PGE2 Expression: A Potential Role of ATF4 in PCOS

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