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 results demonstrate that miR-376a regulates primordial follicle assembly by modulating the expression of proliferating cell nuclear antigen (Pcna), the first microRNA-target mRNA pair that has been reported to regulate mammalianPrimordial follicles assembly and further the understanding of the regulation of primordial folicle assembly.
Abstract: In mammals, the primordial follicle pool, providing all oocytes available to a female throughout her reproductive life, is established perinatally. Dysregulation of primordial follicle assembly results in female reproductive diseases, such as premature ovarian insufficiency and infertility. Female mice lacking Dicer1 (Dicer), a gene required for biogenesis of microRNAs, show abnormal morphology of follicles and infertility. However, the contribution of individual microRNAs to primordial follicle assembly remains largely unknown. Here, we report that microRNA 376a (miR-376a) regulates primordial follicle assembly by modulating the expression of proliferating cell nuclear antigen (Pcna), a gene we previously reported to regulate primordial follicle assembly by regulating oocyte apoptosis in mouse ovaries. miR-376a was shown to be negatively correlated with Pcna mRNA expression in fetal and neonatal mouse ovaries and to directly bind to Pcna mRNA 3' untranslated region. Cultured 18.5 days postcoitum mouse ovaries transfected with miR-376a exhibited decreased Pcna expression both in protein and mRNA levels. Moreover, miR-376a overexpression significantly increased primordial follicles and reduced apoptosis of oocytes, which was very similar to those in ovaries co-transfected with miR-376a and siRNAs targeting Pcna. Taken together, our results demonstrate that miR-376a regulates primordial follicle assembly by modulating the expression of Pcna. To our knowledge, this is the first microRNA-target mRNA pair that has been reported to regulate mammalian primordial follicle assembly and further our understanding of the regulation of primordial follicle assembly.
55 citations
Cites background from "MicroRNAs and ovarian function"
...Female mice lacking Dicer1 (Dicer), a gene required for the biogenesis of vast majority of microRNAs, show abnormal follicle morphology (Lei et al. 2010, Baley & Li 2012)....
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TL;DR: The identification and characterization of differentially expressed miRNAs in the ovaries of pregnant and non-pregnant goats provides important information on the role of miRNA in the regulation of the ovarian development and function.
Abstract: Ovarian follicular development and hormone secretion are complex and coordinated biological processes which will usually be altered during pregnancy. Ovarian function is tightly regulated by a multitude of genes, and also by some specific miRNAs. It is necessary to identify the differentially expressed miRNAs in the ovaries of pregnant and non-pregnant mammals, in order to further understand the role of miRNA-mediated post-transcriptional regulation in mammalian reproduction. Here, we performed a comprehensive search for hircine miRNAs using two small RNA sequencing libraries prepared from the ovaries of pregnant and non-pregnant goats. 617 conserved and 7 putative novel miRNAs were identified in the hircine ovaries. A total of 471 conserved miRNAs (76.34%) were co-expressed in both pregnant and non-pregnant libraries, and 90 pregnancy-specific and 56 non-pregnancy-specific conserved miRNAs were identified. Additionally, 407 unique miRNAs (65.96%) were significantly differentially expressed in the pregnant and non-pregnant libraries, of which 294 were upregulated and 113 were downregulated in the pregnant library compared to the non-pregnant library. Further analysis showed that miR-143 was predicted to bind to the target sequences of Frizzled-6 and -3 receptor genes in the Wnt/beta-catenin signaling pathway, and let-7b may target the Activin receptor I and Smad 2/3 genes in the TGF-beta signaling pathway. The expression level of 5 randomly selected miRNAs were analyzed by quantitative real-time PCR (q-PCR), and the results demonstrated that the expression patterns were consistent with the Solexa sequencing results. The identification and characterization of differentially expressed miRNAs in the ovaries of pregnant and non-pregnant goats provides important information on the role of miRNA in the regulation of the ovarian development and function. This data will be helpful to facilitate studies on the regulation of miRNAs during mammalian reproduction.
54 citations
Cites background from "MicroRNAs and ovarian function"
...Recent research has demonstrated that miRNAs are involved in the regulation of mammalian reproduction, especially the regulation of ovarian function [4,5]....
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...; licensee BioMed Central Commons Attribution License (http://creativec reproduction in any medium, provided the or in target-specific post-transcriptional repression [1-4]....
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TL;DR: The findings suggest that miR-760 represents a potential onco-miR and participates in ovarian cancer carcinogenesis, which highlight its potential as a target for ovarian cancer therapy.
52 citations
TL;DR: The findings suggest that miR-132 is involved in the cAMP signaling pathway and promotes estradiol synthesis via the translational repression of Nurr1 in ovarian GCs.
Abstract: Estrogen synthesis is an important function of the mammalian ovary. Estrogen plays important roles in many biological processes, including follicular development, oocyte maturation and endometrial proliferation, and dysfunctions in estrogen synthesis contribute to the development of polycystic ovary syndrome and premature ovarian failure. Classical signaling cascades triggered by follicle-stimulating hormone induce estrogen synthesis via the upregulation of Cyp19a1 in granulosa cells (GCs). This study aimed to determine the effect of microRNA-132 (miR-132) on estradiol synthesis in GCs. Primary mouse GCs were collected from ovaries of 21-day-old immature ICR mice through follicle puncture. GCs were cultured and treated with the stable cyclic adenosine monophosphate analog 8-Br-cAMP or transfected with miR-132 mimics, Nurr1-specific small interfering RNA oligonucleotides and Flag-Nurr1 plasmids. Concentrations of estradiol and progesterone in culture medium were determined by an automated chemiluminescence-based assay. Quantitative real time PCR and western blot were performed to identify the effect of miR-132 on Cyp19a1, Cyp11a1 and an orphan nuclear receptor-Nurr1 expression in GCs. Direct suppression of Nurr1 via its 3'-untranslated region by miR-132 were further verified using luciferase reporter assays. The expression level of miR-132 in cultured mouse GCs was significantly elevated during 48 h of treatment with 8-Br-cAMP. The synthesis of estradiol increased after the overexpression of miR-132 in mouse GCs. The real-time PCR results demonstrated that miR-132 induced the expression of Cyp19a1 significantly. Nurr1, an orphan nuclear receptor that suppresses Cyp19a1 expression, was found to be a direct target of miR-132. Nurr1 was suppressed by miR-132, as indicated by a luciferase assay and Western blotting. The knockdown of Nurr1 primarily elevated the synthesis of estradiol and partially attenuated the miR-132-induced estradiol elevation, and the ectopic expression of Flag-Nurr1 abrogated the stimulatory effect of miR-132 on estradiol synthesis in mouse GCs. Our findings suggest that miR-132 is involved in the cAMP signaling pathway and promotes estradiol synthesis via the translational repression of Nurr1 in ovarian GCs.
50 citations
Cites background from "MicroRNAs and ovarian function"
...In the ovary, many miRNAs are involved in the proliferation, apoptosis, and differentiation of GCs [12, 13]....
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TL;DR: The results support that diet-induced obesity potentially impairs ovarian function through aberrant gene expression as well as INSR, GSTM and GSTP protein levels.
50 citations
Cites background from "MicroRNAs and ovarian function"
...MiR’s are small (19 – 25 bp) non-coding RNA that can positively or negatively regulate gene expression [81-85]....
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...Up regulation of miR-184 can interfere with AKT action, repressing PI3K action [78, 85]....
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References
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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.
32,946 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: 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
15,374 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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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.
11,624 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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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
5,791 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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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.
4,490 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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