MicroRNAs and ovarian function
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.
Abstract: MicroRNAs (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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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.
247 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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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.
178 citations
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.
110 citations
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.
101 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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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.
97 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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TL;DR: The transcription and processing of mi RNAs determines the abundance and the sequence of mature miRNAs and has important implications for the function of miRN as well as otherRNAs.
Abstract: Micro-RNAs (miRNAs) are a class of approximately 22-nucleotide non-coding RNAs expressed in multicellular organisms. They are first transcribed in a similar manner to pre-mRNAs. The transcripts then go through a series of processing steps, including endonucleolytic cleavage, nuclear export and a strand selection procedure, to yield the single-stranded mature miRNA products. The transcription and processing of miRNAs determines the abundance and the sequence of mature miRNAs and has important implications for the function of miRNAs.
244 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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TL;DR: These studies implicate Dicer1/miRNA mediated posttranscriptional gene regulation in reproductive somatic tissues as critical for the normal development and function of these tissues and for female fertility.
Abstract: The ribonuclease III endonuclease, Dicer1 (also known as Dicer), is essential for the synthesis of the 19–25 nucleotide noncoding RNAs known as micro-RNAs (miRNAs) These miRNAs associate with the RNA-induced silencing complex to regulate gene expression posttranscriptionally by base pairing with 3′untranslated regions of complementary mRNA targets Although it is established that miRNAs are expressed in the reproductive tract, their functional role and effect on reproductive disease remain unknown The studies herein establish for the first time the reproductive phenotype of mice with loxP insertions in the Dicer1 gene (Dicer1fl/fl) when crossed with mice expressing Cre-recombinase driven by the anti-mullerian hormone receptor 2 promoter (Amhr2Cre/+) Adult female Dicer1fl/fl;Amhr2Cre/+ mice displayed normal mating behavior but failed to produce offspring when exposed to fertile males during a 5-month breeding trial Morphological and histological assessments of the reproductive tracts of immature and adult mice indicated that the uterus and oviduct were hypotrophic, and the oviduct was highly disorganized Natural mating of Dicer1fl/fl;Amhr2Cre/+ females resulted in successful fertilization as evidenced by the recovery of fertilized oocytes on d 1 pregnancy, which developed normally to blastocysts in culture Developmentally delayed embryos were collected from Dicer1fl/fl; Amhr2Cre/+ mice on d 3 pregnancy when compared with controls Oviductal transport was disrupted in the Dicer1fl/fl;Amhr2Cre/+ mouse as evidenced by the failure of embryos to enter the uterus on d 4 pregnancy These studies implicate Dicer1/miRNA mediated posttranscriptional gene regulation in reproductive somatic tissues as critical for the normal development and function of these tissues and for female fertility
223 citations
"MicroRNAs and ovarian function" refers background in this paper
...The role of small RNA in the ovary is indicated by the fact that knockout of Dicer, the ribonuclease III which processes pre-small RNA to mature functional small RNA in the ovary resulted in the dysfunction of folliculogenesis, oocyte maturation, ovulation and infertility [30-34]....
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TL;DR: The following studies are the first to describe the extent of miRNA expression within ovarian granulosa cells and theFirst to demonstrate that LH/hCG regulates the expression of select miRNAs, which affect posttranscriptional gene regulation within these cells.
Abstract: MicroRNAs (miRNAs) mediate posttranscriptional gene regulation by binding to the 3' untranslated region of messenger RNAs to either inhibit or enhance translation. The extent and hormonal regulation of miRNA expression by ovarian granulosa cells and their role in ovulation and luteinization is unknown. In the present study, miRNA array analysis was used to identify 212 mature miRNAs as expressed and 13 as differentially expressed in periovulatory granulosa cells collected before and after an ovulatory dose of hCG. Two miRNAs, Mirn132 and Mirn212 (also known as miR-132 and miR-212), were found to be highly upregulated following LH/hCG induction and were further analyzed. In vivo and in vitro temporal expression analysis by quantitative RT-PCR confirmed that LH/hCG and cAMP, respectively, increased transcription of the precursor transcript as well as the mature miRNAs. Locked nucleic acid oligonucleotides complementary to Mirn132 and Mirn212 were shown to block cAMP-mediated mature miRNA expression and function. Computational analyses indicated that 77 putative mRNA targets of Mirn132 and Mirn212 were expressed in ovarian granulosa cells. Furthermore, upon knockdown of Mirn132 and Mirn212, a known target of Mirn132, C-terminal binding protein 1, showed decreased protein levels but no change in mRNA levels. The following studies are the first to describe the extent of miRNA expression within ovarian granulosa cells and the first to demonstrate that LH/hCG regulates the expression of select miRNAs, which affect posttranscriptional gene regulation within these cells.
221 citations
"MicroRNAs and ovarian function" refers background in this paper
...It is suggested that miR-132 and miR212 play an important role as post-transcriptional regulators in granulosa cells, as computational analysis has identified 77 putative mRNA as potential targets of miR-212, and miR-132 in granulosa cells [46]....
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...In addition, it was also demonstrated that granulosa cells collected immediately before and 4 h after the ovulatory surge of LH/hCG exhibit differential miRNA expression patterns [46], suggesting a role in ovulation....
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...Interestingly, knockdown of both miR-212 and miR-132 resulted in decreased protein levels of CTBP1 but with no change in mRNA levels [46]....
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...Recent evidence supports the role of luteinizing hormone (LH)/human chorionic gonadotropin (hCG) in the regulation of miRNA expression [46]....
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...A previous study has reported 13 miRNAs which are differentially expressed in murine granulosa cells before and 4 h after the hCG/LH surge, with miR132, miR-212, and miR-21 being the top three highly up-regulated [46]....
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TL;DR: This study is the first to implicate the antiapoptotic Mir21 (an oncogenic miRNA) as playing a clear physiologic role in normal tissue function and plays a role in the induction of ovarian granulosa cell apoptosis.
Abstract: MicroRNAs (miRNAs) play important roles in many developmental processes, including cell differentiation and apoptosis. Transition of proliferative ovarian granulosa cells to terminally differentiated luteal cells in response to the ovulatory surge of luteinizing hormone (LH) involves rapid and pronounced changes in cellular morphology and function. MicroRNA 21 (miR-21, official symbol Mir21) is one of three highly LH-induced miRNAs in murine granulosa cells, and here we examine the function and temporal expression of Mir21 within granulosa cells as they transition to luteal cells. Granulosa cells were transfected with blocking (2′-O-methyl) and locked nucleic acid (LNA-21) oligonucleotides, and mature Mir21 expression decreased to one ninth and one twenty-seventh of its basal expression, respectively. LNA-21 depletion of Mir21 activity in cultured granulosa cells induced apoptosis. In vivo, follicular granulosa cells exhibit a decrease in cleaved caspase 3, a hallmark of apoptosis, 6 h after the LH/human chorionic gonadotropin surge, coincident with the highest expression of mature Mir21. To examine whether Mir21 is involved in regulation of apoptosis in vivo, mice were treated with a phospho thioate-modified LNA-21 oligonucleotide, and granulosa cell apoptosis was examined. Apoptosis increased in LNA-21-treated ovaries, and ovulation rate decreased in LNA-21-treated ovaries, compared with their contralateral controls. We have examined a number of Mir21 apoptotic target transcripts identified in other systems; currently, none of these appear to play a role in the induction of ovarian granulosa cell apoptosis. This study is the first to implicate the antiapoptotic Mir21 (an oncogenic miRNA) as playing a clear physiologic role in normal tissue function.
220 citations
"MicroRNAs and ovarian function" refers background or result in this paper
...Further study by the same group revealed that when miR-21 expression was decreased to one twenty-seventh of its basal expression with locked nucleic acid (LNA-21) oligonucleotide transfection, apoptosis was induced in granulosa cells [55]....
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...Similar results were observed in their in vivo study with a miR21 inhibitor, although the targets of miR-21 suppressing apoptosis in granulosa cells are still to be identified [55]....
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TL;DR: It is demonstrated that miRNAs can control reproductive functions resulting in enhanced or inhibited release of ovarian progestagen, androgen and estrogen, the first demonstration that miRNA‐mediated effects could be potentially used for regulation of reproductive processes.
Abstract: The aim of our studies was to identify miRNAs affecting the release of the major ovarian steroid hormones progestagen, androgen and estrogen by human ovarian cells. The effect of transfection of cultured primary ovarian granulosa cells with 80 different gene constructs encoding human pre-miRNAs on release of progesterone, testosterone and estradiol was evaluated by enzyme immunoassay. In addition, effect of two selected antisense constructs blocking corresponding miRNA on progesterone release was tested. Efficiency of transfection (incorporation transfection reagent) and silencing of marker substances (GAPDH mRNA, GAPDH and CREB-1) were validated by fluorescent microscopy, real-time reverse transcription-PCR analysis and immunocytochemical analysis. Thirty-six out of 80 tested miRNA constructs resulted in inhibition of progesterone release in granulosa cells, and 10 miRNAs promoted progesterone release. Transfected of cells with antisense constructs to two selected miRNAs blocking progesterone release induced increase in progesterone output. Fifty-seven miRNAs tested inhibited testosterone release, and only one miRNA enhanced testosterone output. Fifty-one miRNAs suppressed estradiol release, while none of the miRNAs tested stimulated it. This is the first demonstration that miRNAs can control reproductive functions resulting in enhanced or inhibited release of ovarian progestagen, androgen and estrogen. We hypothesize that such miRNA-mediated effects could be potentially used for regulation of reproductive processes, including fertility, and for treatment of reproductive and other steroid-dependent disorders.
191 citations
"MicroRNAs and ovarian function" refers background or methods or result in this paper
...In addition, over-expression of miR-24, miR-25, miR-122, miR-182, miR-18, miR-125, and miR-32 resulted in a rise in progesterone release, consistent with the process of luteinization [52]....
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...It was hypothesized that these miRNAs act as physiological suppressors of general secretory activity [52]....
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...Using a large-scale platform approach, it was recently shown that 51 microRNAs have suppressive effects on estradiol production [52]....
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