This gene is downstream of YAP of the Hippo signaling pathway.
YAP mediates crosstalk between the Hippo and PI(3)K-TOR pathways by suppressing PTEN via?miR-29. Tumaneng K et al. Organ development is a complex process governed by the interplay of several signalling pathways that have critical functions in the regulation of cell growth and proliferation. Over the past years, the Hippo pathway has emerged as a key regulator of organ size. Perturbation of this pathway has been shown to play important roles in tumorigenesis. YAP, the main downstream target of the mammalian Hippo pathway, promotes organ growth, yet the underlying molecular mechanism of this regulation remains unclear. Here we provide evidence that YAP activates the mammalian target of rapamycin (mTOR), a major regulator of cell growth. We have identified the tumour suppressor PTEN, an upstream negative regulator of mTOR, as a critical mediator of YAP in mTOR regulation. We demonstrate that YAP downregulates PTEN by inducing miR-29 to inhibit PTEN translation. Last, we show that PI(3)K-mTOR is a pathway modulated by YAP to regulate cell size, tissue growth and hyperplasia. Our studies reveal a functional link between Hippo and PI(3)K-mTOR, providing a molecular basis for the coordination of these two pathways in organ size regulation.
NCBI Summary:
microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]
General function
Cell proliferation, RNA processing
Comment
Cellular localization
Cytoplasmic
Comment
Ovarian function
Follicle development
Comment
MiR-29 regulates the function of goat granulosa cell by targeting PTX3 via the PI3K/AKT/mTOR and Erk1/2 signaling pathways. Wang P et al. (2020) PTX3, a member of the pentraxin protein family, plays important roles in ovulation as a marker of cumulus cell-oocyte complex expansion. However, the expression and function of PTX3 in goat ovarian GCs remain unclear. We isolated GCs from small and large follicles and found that PTX3 expression was significantly decreased and miR-29 mRNA expression was significantly increased during the growth of antral follicles. MiR-29 decreased PTX3 expression by targeting its 3' untranslated. Furthermore, miR-29 promoted GC proliferation, suppressed steroidogenesis and apoptosis by targeting PTX3 via the activation of the PI3K/AKT/mTOR and Erk1/2 signaling pathways. Treatment with inhibitors also verified these results. Meanwhile, we found that PI3K/AKT/mTOR and Erk1/2 signaling pathways had different role in secretion of E2 and P4 by regulating differently various steroidogenic enzyme (CYP19A1, CYP11A1, StAR and HSD3B) expression. These outcomes indicate the potential role of PTX3 in goat follicular growth and atresia.//////////////////
MiR-29a regulates the proliferation, aromatase expression, and estradiol biosynthesis of human granulosa cells in polycystic ovary syndrome. Li Y et al. (2019) Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility in reproductive-aged women; however, its etiology remains poorly understood. This study aimed to reveal the role of miR-29a in PCOS. MiR-29a levels were measured in the granulosa cells (GCs) of forty-seven PCOS patients and forty-seven controls. A receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic value of miR-29a in non-hyperandrogenism PCOS. MiR-29a was overexpressed in KGN and COV434 cells to examine its roles in proliferation, cell-cycle progression, and steroidogenesis. MiR-29a was significantly down-regulated in PCOS patients, and associated with an increased antral follicle count. The ROC curve showed a major separation between PCOS patients and controls. MiR-29a overexpression in KGN and COV434 cells inhibited cell proliferation, arrested cell-cycle progression, and decreased aromatase expression and estradiol production. These findings suggest that miR-29a is involved in GC proliferation and steroidogenesis, providing insights into PCOS pathogenesis.//////////////////
Expression regulated by
FSH, Growth Factors/ cytokines
Comment
TGF-β1 increases lysyl oxidase by reducing miR-29a in human granulosa-lutein cells. Fang Y et al. (2016) Lysyl oxidase (LOX), a key enzyme in the formation and stabilization of the extracellular matrix, is expressed in granulosa cells and plays a critical role in the regulation of granulosa cell differentiation, oocyte maturation and ovulation. To date, the regulation of LOX expression in human granulosa cells remains largely unknown. In the present study, using primary and immortalized human granulosa-lutein cells, we demonstrated that transforming growth factor (TGF)-β1 up-regulated LOX expression and down-regulated microRNA-29a (miR-29a) expression via a TGF-β type I receptor-mediated signaling pathway. Additionally, we showed that miR-29a down-regulated the expression of LOX in both types of cells. Furthermore, the down-regulation of miR-29a contributed to the TGF-β1-induced increase in LOX expression because the inhibition of miR-29a with a miR-29a inhibitor not only reversed the miR-29a-induced down-regulation of LOX but also enhanced the TGF-β1-induced up-regulation of LOX. Our findings suggest that TGF-β1 and miR-29a may play essential roles in the regulation of extracellular matrix remodeling during the periovulatory phase.//////////////////
Follicle-stimulating hormone regulation of microRNA expression on progesterone production in cultured rat granulosa cells. Yao N et al. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally by interacting with the 3' untranslated regions of their target mRNAs. Previously, miRNAs have been shown to regulate genes involved in cell growth, apoptosis, and differentiation, but their role in ovarian granulosa cell follicle-stimulating hormone (FSH)-stimulated steroidogenesis is unclear. Here we show that expression of 31 miRNAs is altered during FSH-mediated progesterone secretion of cultured granulosa cells. Specifically, 12 h after FSH treatment, miRNAs mir-29a and mir-30d were significantly down-regulated. However, their expression increased after 48 h. Bioinformatic analysis used to predict potential targets of mir-29a and mir-30d revealed a wide array of potential mRNA target genes, including those encoding genes involved in multiple signaling pathways. Taken together, our results pointed to a novel mechanism for the pleiotropic effects of FSH.//////
Small decreases followed by a large increase between 24 and 48h.
Ovarian localization
Cumulus, Granulosa
Comment
MicroRNAs: new candidates for the regulation of the human cumulus-oocyte complex. Assou S 2013 et al.
STUDY QUESTION
What is the expression pattern of microRNAs (miRNAs) in human cumulus-oocyte complexes (COCs)?
SUMMARY ANSWER
Several miRNAs are enriched in cumulus cells (CCs) or oocytes, and are predicted to target genes involved in biological functions of the COC.
WHAT IS KNOWN ALREADY
The transcriptional profiles of human MII oocytes and the surrounding CCs are known. However, very limited data are available about post-transcriptional regulators, such as miRNAs. This is the first study focussing on the identification and quantification of small RNAs, including miRNAs, in human oocytes and CCs using a deep-sequencing approach.
STUDY DESIGN, SIZE, DURATION
MII oocytes and CCs were collected from women who underwent IVF.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Using the Illumina/deep-sequencing technology, we analyzed the small RNAome of pooled MII oocytes (n = 24) and CC samples (n = 20). The mRNA targets of CC and MII oocyte miRNAs were identified using in silico prediction algorithms. Using oligonucleotide microarrays, genome-wide gene expression was studied in oocytes (10 pools of 19 3 oocytes/each) and 10 individual CC samples. TaqMan miRNA assays were used to confirm the sequencing results in independent pools of MII oocytes (3 pools of 8 3 oocytes/each) and CC samples (3 pools of 7 3 CCs/each). The functional role of one miRNA, MIR23a, was assessed in primary cultures of human CCs.
MAIN RESULTS AND THE ROLE OF CHANCE
Deep sequencing of small RNAs yielded more than 1 million raw reads. By mapping reads with a single location to the human genome, known miRNAs that were abundant in MII oocytes (MIR184, MIR100 and MIR10A) or CCs (MIR29a, MIR30d, MIR21, MIR93, MIR320a, MIR125a and the LET7 family) were identified. Predicted target genes of the oocyte miRNAs were associated with the regulation of transcription and cell cycle, whereas genes targeted by CC miRNAs were involved in extracellular matrix and apoptosis. Comparison of the predicted miRNA target genes and mRNA microarray data resulted in a list of 224 target genes that were differentially expressed in MII oocytes and CCs, including PTGS2, CTGF and BMPR1B that are important for cumulus-oocyte communication. Functional analysis using primary CC cultures revealed that BCL2 and CYP19A1 mRNA levels were decreased upon MIR23a overexpression.
LIMITATIONS, REASONS FOR CAUTION
Only known miRNAs were investigated in the present study on COCs. Moreover, the source of the material is MII oocytes that failed to fertilize.
WIDER IMPLICATIONS OF THE FINDINGS
The present findings suggest that miRNA could play a role in the regulation of the oocyte and CC crosstalk.
STUDY FUNDING/COMPETING INTEREST(S)
This work was partially supported by a grant from Ferring Pharmaceuticals. The authors of the study have no conflict of interest to report.
TRIAL REGISTRATION NUMBER
Not applicable.
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Follicle stages
Antral
Comment
Identification and characterization of miRNAs expressed in the bovine ovary. Hossain MM et al. ABSTRACT: BACKGROUND: MicroRNAs are the major class of gene-regulating molecules playing diverse roles through sequence complementarity to target mRNAs at post-transcriptional level. Tightly regulated expression and interaction of a multitude of genes for ovarian folliculogenesis could be regulated by these miRNAs. Identification of them is the first step towards understanding miRNA-guided gene regulation in different biological functions. Despite increasing efforts in miRNAs identification across various species and diverse tissue types, little is known about bovine ovarian miRNAs. Here, we report the identification and characterization of miRNAs expressed in the bovine ovary through cloning, expression analysis and target prediction. RESULTS: The miRNA library (5'-independent ligation cloning method), which was constructed from bovine ovary in this study, revealed cloning of 50 known and 24 novel miRNAs. Among all identified miRNAs, 38 were found to be new for bovine and were derived from 43 distinct loci showing characteristic secondary structure. While 22 miRNAs precursor loci were found to be well conserved in more than one species, 16 were found to be bovine specific. Most of the miRNAs were cloned multiple times, in which let-7a, let-7b, let-7c, miR-21, miR-23b, miR-24, miR-27a, miR-126 and miR-143 were cloned 10, 28, 13, 4, 11, 7, 6, 4 and 11 times, respectively. Expression analysis of all new and some annotated miRNAs in different intra-ovarian structures and in other multiple tissues showed that some were present ubiquitously while others were differentially expressed among different tissue types. Bta-miR-29a was localized in the follicular cells at different developmental stages in the cyclic ovary. Bio-informatics prediction, screening and Gene Ontology analysis of miRNAs targets identified several biological processes and pathways underlying the ovarian function. CONCLUSIONS: Results of this study suggest the presence of miRNAs in the bovine ovary, thereby elucidate their potential role in regulating diverse molecular and physiological pathways underlying the ovarian functionality. This information will give insights into bovine ovarian miRNAs, which can be further characterized for their role in follicular development and female fertility as well.