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Journal ArticleDOI

MicroRNAs and ovarian function

09 Feb 2012-Journal of Ovarian Research (BioMed Central)-Vol. 5, Iss: 1, pp 8-8

TL;DR: The current understanding of miRNA biogenesis, the role and mechanism that miRNAs play in post-transcriptional gene expression regulation, and specifically the current evidence of mi RNA involvement in ovarian development and function are reviewed.

AbstractMicroRNAs (miRNAs) are a class of small non-coding RNAs which function in gene regulation with an important role in cell proliferation, maturation, and activity. The regulatory role of these small RNA molecules has recently begun to be explored in ovarian cells, uncovering their influence on gonadal development, steroidogenesis, apoptosis, ovulation, and corpus luteum development. This emerging area of research has extended and reshaped our understanding on how ovarian function is regulated. Here, we review the current understanding of miRNA biogenesis, the role and mechanism that miRNAs play in post-transcriptional gene expression regulation, and specifically the current evidence of miRNA involvement in ovarian development and function. Future comprehensive understanding of the role of miRNAs in the ovary in both physiological and pathological conditions may offer new treatment strategies for infertility and other ovarian disorders.

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Citations
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Journal ArticleDOI
04 Nov 2013-PLOS ONE
TL;DR: The presence of exosome or non-exosome mediated transfer of miRNA in the bovine follicular fluid, and oocyte growth dependent variation in extra-cellular miRNA signatures in the follicular environment is demonstrated for the first time.
Abstract: Cell-cell communication within the follicle involves many signaling molecules, and this process may be mediated by secretion and uptake of exosomes that contain several bioactive molecules including extra-cellular miRNAs. Follicular fluid and cells from individual follicles of cattle were grouped based on Brilliant Cresyl Blue (BCB) staining of the corresponding oocytes. Both Exoquick precipitation and differential ultracentrifugation were used to separate the exosome and non-exosomal fraction of follicular fluid. Following miRNA isolation from both fractions, the human miRCURY LNA™ Universal RT miRNA PCR array system was used to profile miRNA expression. This analysis found that miRNAs were present in both exosomal and non-exosomal fraction of bovine follicular fluid. We found 25 miRNAs differentially expressed (16 up and 9 down) in exosomes and 30 miRNAs differentially expressed (21 up and 9 down) in non-exosomal fraction of follicular fluid in comparison of BCB- versus BCB+ oocyte groups. Expression of selected miRNAs was detected in theca, granulosa and cumulus oocyte complex. To further explore the potential roles of these follicular fluid derived extra-cellular miRNAs, the potential target genes were predicted, and functional annotation and pathway analysis revealed most of these pathways are known regulators of follicular development and oocyte growth. In order to validate exosome mediated cell-cell communication within follicular microenvironment, we demonstrated uptake of exosomes and resulting increase of endogenous miRNA level and subsequent alteration of mRNA levels in follicular cells in vitro. This study demonstrates for the first time, the presence of exosome or non-exosome mediated transfer of miRNA in the bovine follicular fluid, and oocyte growth dependent variation in extra-cellular miRNA signatures in the follicular environment.

206 citations


Cites background from "MicroRNAs and ovarian function"

  • ...During the dynamic phase of follicular development and oocyte maturation, miRNAs play an important role by coordinating the expression of genes in a spatial and temporal specific manner [21,22]....

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Journal ArticleDOI
TL;DR: This study identified a series of exosomal microRNAs that are highly represented in human FF and are involved in follicular maturation and could represent noninvasive biomarkers of oocyte quality in assisted reproductive technology.
Abstract: Objective To characterize well-represented microRNAs in human follicular fluid (FF) and to ascertain whether they are cargo of FF exosomes and whether they are involved in the regulation of follicle maturation. Design FF exosomes were characterized by nanosight, flow cytometry, and exosome-specific surface markers. Expression microRNA profiles from total and exosomal FF were compared with those from plasma of the same women. Setting University laboratory and an IVF center. Patient(s) Fifteen healthy women who had undergone intracytoplasmic sperm injection. Intervention(s) None. Main Outcome Measure(s) TaqMan low-density array to investigate the expression profile of 384 microRNAs; DataAssist and geNorm for endogenous control identification; significance analysis of microarrays to identify differentially expressed microRNAs; nanosight, flow-cytometry, and bioanalyzer for exosome characterization; bioinformatic tools for microRNAs target prediction, gene ontology, and pathway analysis. Result(s) We identified 37 microRNAs upregulated in FF as compared with plasma from the same women. Thirty-two were carried by microvesicles that showed the well-characterized exosomal markers CD63 and CD81. These FF microRNAs are involved in critically important pathways for follicle growth and oocyte maturation. Specifically, nine of them target and negatively regulate mRNAs expressed in the follicular microenvironment encoding inhibitors of follicle maturation and meiosis resumption. Conclusion(s) This study identified a series of exosomal microRNAs that are highly represented in human FF and are involved in follicular maturation. They could represent noninvasive biomarkers of oocyte quality in assisted reproductive technology.

131 citations


Journal ArticleDOI
TL;DR: It is demonstrated that miR‐133b down‐regulates Foxl2 expression in granulosa cells by directly targeting the 3′UTR, thus inhibiting the Foxl 2‐mediated transcriptional repression of StAR and CYP19A1 to promote estradiol production.
Abstract: Forkhead L2 (Foxl2) is expressed in ovarian granulosa cells and participates in steroidogenesis by transcriptionally regulating target genes such as steroidogenic acute regulatory protein (StAR) and CYP19A1. In this study, a direct link between microRNA-133b (miR-133b) and Foxl2-mediated estradiol release in granulosa cells was established. miR-133b was involved in follicle-stimulating hormone (FSH)-induced estrogen production. Luciferase assays confirmed that miR-133b was bound to the 3′ untranslated region (3′UTR) of Foxl2 mRNA. Consistent with this finding, miR-133b overexpression reduced the Foxl2 levels. Furthermore, miR-133b inhibited Foxl2 binding to the StAR and CYP19A1 promoter sequences. These results demonstrate that miR-133b down-regulates Foxl2 expression in granulosa cells by directly targeting the 3′UTR, thus inhibiting the Foxl2-mediated transcriptional repression of StAR and CYP19A1to promote estradiol production.

88 citations


Cites background from "MicroRNAs and ovarian function"

  • ...The effects of miRNAs on ovarian function primarily occur through their actions on somatic cells, such as granulosa cells [12]....

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Journal ArticleDOI
TL;DR: Serum miRNAs are differentially expressed between PCOS patients and controls, and bioinformatics analysis indicated that the predicted targets function of the three miRN as mainly involved in the metastasis, cell cycle, apoptosis and endocrine.
Abstract: Background: Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women of reproductive age, is characterized by polycystic ovaries, chronic anovulation, hyperandrogenism and insulin resistance. Despite the high prevalence of hyperandrogenemia, a definitive endocrine marker for PCOS has so far not been identified. Circulating miRNAs have recently been shown to serve as diagnostic/prognostic biomarkers in patients with cancers. Our current study focused on the altered expression of serum miRNAs and their correlation with PCOS. Method and Results: We systematically used the TaqMan Low Density Array followed by individual quantitative reverse transcription polymerase chain reaction assays to identify and validate the expression of serum miRNAs of PCOS patients. The expression levels of three miRNAs (miR-222, miR-146a and miR-30c) were significantly increased in PCOS patients with respect to the controls in our discovery evaluation and followed validation. The area under the receiver operating characteristic (ROC) curve (AUC) is 0.799, 0.706, and 0.688, respectively. The combination of the three miRNAs using multiple logistic regression analysis showed a larger AUC (0.852) that was more efficient for the diagnosis of PCOS. In addition, logistic binary regression analyses show miR-222 is positively associated with serum insulin, while miR-146a is negatively associated with serum testosterone. Furthermore, bioinformatics analysis indicated that the predicted targets function of the three miRNAs mainly involved in the metastasis, cell cycle, apoptosis and endocrine. Conclusion: Serum miRNAs are differentially expressed between PCOS patients and controls. We identified and validated a class of three serum miRNAs that could act as novel non-invasive biomarkers for diagnosis of PCOS. These miRNAs may be involved in the pathogenesis of PCOS.

82 citations


Journal ArticleDOI
TL;DR: This review considers recent advances in the identification of miRNAs involved in the regulation of ovarian function as well as the possible influence ofmiRNAs on ovarian-derived disorders, such as ovarian cancer, polycystic ovarian syndrome and premature ovarian failure.
Abstract: MicroRNAs (miRNAs) are endogenous, small, noncoding single-stranded RNA molecules approximately 22 nucleotides in length. miRNAs are involved in the post-transcriptional regulation of various important cellular physiological and pathological processes, including cell proliferation, differentiation, apoptosis, and hormone biosynthesis and secretion. Ovarian follicles are the key functional units of female reproduction, and the development of these follicles is a complex and precise process accompanied by oocyte maturation as well as surrounding granulosa cell proliferation and differentiation. Numerous miRNAs expressed in the ovary regulate ovarian follicle growth, atresia, ovulation and steroidogenesis and play an important role in ovarian disorders. This review considers recent advances in the identification of miRNAs involved in the regulation of ovarian function as well as the possible influence of miRNAs on ovarian-derived disorders, such as ovarian cancer, polycystic ovarian syndrome and premature ovarian failure. An improved understanding of the regulation of ovarian function by miRNAs may shed light on new strategies for ovarian biology and ovarian disorders.

81 citations


Cites background from "MicroRNAs and ovarian function"

  • ...Folliculogenesis and steroidogenesis are complex processes involving intraovarian gene expression, signaling pathways, and endocrine and paracrine factors [8, 9]....

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  • ...In each stage of follicle development, different growth factors contribute to stage-specific functions in different cell types [8, 9]....

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References
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Journal ArticleDOI
23 Jan 2004-Cell
TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.
Abstract: MicroRNAs (miRNAs) are endogenous ∼22 nt RNAs that can play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression. Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.

30,422 citations


"MicroRNAs and ovarian function" refers background in this paper

  • ...The genes that encode miRNAs, which comprise a class of naturally occurring, small non-coding RNAs, are generally transcribed by RNA polymerase II, processed into short hairpin RNAs by the enzyme Drosha and its RNA-binding cofactor DiGeorge syndrome critical region gene 8 (DGCR8), as shown in Figure 1 [4-7]....

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Journal ArticleDOI
19 Feb 1998-Nature
TL;DR: To their surprise, it was found that double-stranded RNA was substantially more effective at producing interference than was either strand individually, arguing against stochiometric interference with endogenous mRNA and suggesting that there could be a catalytic or amplification component in the interference process.
Abstract: Experimental introduction of RNA into cells can be used in certain biological systems to interfere with the function of an endogenous gene Such effects have been proposed to result from a simple antisense mechanism that depends on hybridization between the injected RNA and endogenous messenger RNA transcripts RNA interference has been used in the nematode Caenorhabditis elegans to manipulate gene expression Here we investigate the requirements for structure and delivery of the interfering RNA To our surprise, we found that double-stranded RNA was substantially more effective at producing interference than was either strand individually After injection into adult animals, purified single strands had at most a modest effect, whereas double-stranded mixtures caused potent and specific interference The effects of this interference were evident in both the injected animals and their progeny Only a few molecules of injected double-stranded RNA were required per affected cell, arguing against stochiometric interference with endogenous mRNA and suggesting that there could be a catalytic or amplification component in the interference process

14,583 citations


"MicroRNAs and ovarian function" refers background in this paper

  • ...MicroRNAs (miRNAs) are small (19-25 bp) RNAs that diversely regulate gene expression through their decrease of messenger RNA (mRNA) stability or translation [1-3]....

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Journal ArticleDOI
14 Jan 2005-Cell
TL;DR: In a four-genome analysis of 3' UTRs, approximately 13,000 regulatory relationships were detected above the estimate of false-positive predictions, thereby implicating as miRNA targets more than 5300 human genes, which represented 30% of the gene set.
Abstract: We predict regulatory targets of vertebrate microRNAs (miRNAs) by identifying mRNAs with conserved complementarity to the seed (nucleotides 2-7) of the miRNA. An overrepresentation of conserved adenosines flanking the seed complementary sites in mRNAs indicates that primary sequence determinants can supplement base pairing to specify miRNA target recognition. In a four-genome analysis of 3' UTRs, approximately 13,000 regulatory relationships were detected above the estimate of false-positive predictions, thereby implicating as miRNA targets more than 5300 human genes, which represented 30% of our gene set. Targeting was also detected in open reading frames. In sum, well over one third of human genes appear to be conserved miRNA targets.

11,029 citations


"MicroRNAs and ovarian function" refers background in this paper

  • ...It has been estimated that 30-90% of messenger RNAs may be subjected to miRNA regulation, and individual miRNAs are predicted to target up to several hundred genes [14-16]....

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Journal ArticleDOI
TL;DR: The results indicate that miRNAs are extensively involved in cancer pathogenesis of solid tumors and support their function as either dominant or recessive cancer genes.
Abstract: Small noncoding microRNAs (miRNAs) can contribute to cancer development and progression and are differentially expressed in normal tissues and cancers From a large-scale miRnome analysis on 540 samples including lung, breast, stomach, prostate, colon, and pancreatic tumors, we identified a solid cancer miRNA signature composed by a large portion of overexpressed miRNAs Among these miRNAs are some with well characterized cancer association, such as miR-17-5p, miR-20a, miR-21, miR-92, miR-106a, and miR-155 The predicted targets for the differentially expressed miRNAs are significantly enriched for protein-coding tumor suppressors and oncogenes (P < 00001) A number of the predicted targets, including the tumor suppressors RB1 (Retinoblastoma 1) and TGFBR2 (transforming growth factor, beta receptor II) genes were confirmed experimentally Our results indicate that miRNAs are extensively involved in cancer pathogenesis of solid tumors and support their function as either dominant or recessive cancer genes

5,538 citations


"MicroRNAs and ovarian function" refers background in this paper

  • ...In addition, miRNAs may also increase translation of specific mRNAs in a manner dependent on the cell cycle [25], and a large number of miRNAs may be expressed in a tissue-specific manner [26]....

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Journal ArticleDOI
20 Feb 2009-Cell
TL;DR: This work has revealed unexpected diversity in their biogenesis pathways and the regulatory mechanisms that they access, which has direct implications for fundamental biology as well as disease etiology and treatment.
Abstract: Over the last decade, ∼20–30 nucleotide RNA molecules have emerged as critical regulators in the expression and function of eukaryotic genomes. Two primary categories of these small RNAs—short interfering RNAs (siRNAs) and microRNAs (miRNAs)—act in both somatic and germline lineages in a broad range of eukaryotic species to regulate endogenous genes and to defend the genome from invasive nucleic acids. Recent advances have revealed unexpected diversity in their biogenesis pathways and the regulatory mechanisms that they access. Our understanding of siRNA- and miRNA-based regulation has direct implications for fundamental biology as well as disease etiology and treatment.

4,119 citations


"MicroRNAs and ovarian function" refers background in this paper

  • ...Recognition is thought to mainly involve base pairing of miRNA nucleotides 2-8, representing the seed sequence [13]....

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