Oocyte regulation of anti-Müllerian hormone expression in granulosa cells during ovarian follicle development in mice

Previous evidence fromin vitrostudies suggests specific roles for a subset of miRNAs, including miR-21, miR-23a, miR-145, miR-503, miR-224, miR-383, miR-378, miR-132, and miR-212, in regulating ovarian follicle development. The objective of this study was to determine changes in the levels of these miRNAs in relation to follicle selection, maturation, and ovulation in the monovular equine ovary. In Experiment 1, follicular fluid was aspirated during ovulatory cycles from the dominant (DO) and largest subordinate (S) follicles of an ovulatory wave and the dominant (DA) follicle of a mid-cycle anovulatory wave (n=6 mares). Follicular fluid levels of progesterone and estradiol were lower (P<0.01) in S follicles than in DO follicles, whereas mean levels of IGF1 were lower (P<0.01) in S and DA follicles than in DO follicles. Relative to DO and DA follicles, S follicles had higher (P≤0.01) follicular fluid levels of miR-145 and miR-378. In Experiment 2, follicular fluid and granulosa cells were aspirated from dominant follicles before (DO) and 24 h after (L) administration of an ovulatory dose of hCG (n=5 mares/group). Relative to DO follicles, L follicles had higher follicular fluid levels of progesterone (P=0.05) and lower granulosa cell levels ofCYP19A1andLHCGR(P<0.005). Levels of miR-21, miR-132, miR-212, and miR-224 were increased (P<0.05) in L follicles; this was associated with reduced expression of the putative miRNA targets,PTEN,RASA1, andSMAD4. These novel results may indicate a physiological involvement of miR-21, miR-145, miR-224, miR-378, miR-132, and miR-212 in the regulation of cell survival, steroidogenesis, and differentiation during follicle selection and ovulation in the monovular ovary.

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SMAD3 regulates the diverse functions of rat granulosa cells relating to the FSHR/PKA signaling pathway

Reproduction ◽

10.1530/rep-12-0325 ◽

2013 ◽

Vol 146 (2) ◽

pp. 169-179 ◽

Cited By ~ 15

Author(s):

Yexia Li ◽

Yujie Jin ◽

Yuxia Liu ◽

Chunyan Shen ◽

Jingxia Dong ◽

...

Keyword(s):

Granulosa Cells ◽

Transforming Growth Factor ◽

Ovarian Follicle ◽

Transforming Growth Factor Β ◽

Female Rats ◽

Nuclear Antigen ◽

Follicle Development ◽

Sprague Dawley ◽

Ovarian Follicle Development ◽

Estrogen Production

The function of Smad3, a downstream signaling protein of the transforming growth factor β (TGFβ) pathway, in ovarian follicle development remains to be elucidated. The effects of Smad3 on ovarian granulosa cells (GCs) in rat were studied. Female rats (21 days of age Sprague–Dawley) received i.p. injections of pregnant mare serum gonadotropin, and GCs were harvested for primary culture 48 h later. These cells were engineered to overexpress or knockdown Smad3, which were validated by immunohistochemistry and western blot. The expression of proliferating cell nuclear antigen (PCNA), cyclin D2, TGFβ receptor II (TGFβRII), protein kinase A (PKA), and FSH receptor (FSHR) was also detected by western blotting. Cell cycle and apoptosis of GCs were assayed by flow cytometry. The level of estrogen secreted by GCs was detected by ELISA. Smad3 overexpression promoted estrogen production and proliferation while inhibiting apoptosis of GCs. Reduction in Smad3 by RNAi resulted in reduced estrogen production and proliferation and increased apoptosis of GCs. Manipulation of Smad3 expression also resulted in changes in FSHR and PKA expression, suggesting that the effects of Smad3 on follicle development are related to FSHR-mediated cAMP signaling.

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TMCO1 is essential for ovarian follicle development by regulating ER Ca2+ store of granulosa cells

Cell Death and Differentiation ◽

10.1038/s41418-018-0067-x ◽

2018 ◽

Vol 25 (9) ◽

pp. 1686-1701 ◽

Cited By ~ 13

Author(s):

Zhongshuai Sun ◽

Hui Zhang ◽

Xi Wang ◽

Qiao-Chu Wang ◽

Chuanchao Zhang ◽

...

Keyword(s):

Granulosa Cells ◽

Ovarian Follicle ◽

Follicle Development ◽

Ovarian Follicle Development

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Yes-associated protein (YAP) is required in maintaining normal ovarian follicle development and function

10.1101/406256 ◽

2018 ◽

Cited By ~ 1

Author(s):

Michele R. Plewes ◽

Xiaoying Hou ◽

Pan Zhang ◽

Jennifer Wood ◽

Andrea Cupp ◽

...

Keyword(s):

Granulosa Cells ◽

Ovarian Follicle ◽

Hippo Pathway ◽

Critical Role ◽

Ovarian Follicles ◽

Follicle Development ◽

Hippo Signaling ◽

Ovarian Follicle Development ◽

The Hippo Pathway

ABSTRACTYes-associated protein (YAP) is one of the major components of the Hippo signaling pathway, also known as the Salvador/Warts/Hippo (SWH) pathway. Although the exact extracellular signal that controls the Hippo pathway is currently unknown, increasing evidence supports a critical role of the Hippo pathway in embryonic development, regulation of organ size, and carcinogenesis. The ovary is one of few adult tissues that exhibit cyclical changes. Ovarian follicles, the basic units of ovary, are composed of a single oocyte surrounded by expanding layers of granulosa and theca cells. Granulosa cells (GCs) produce sex steroids and growth factors, which facilitate the development of the follicle and maturation of the oocyte. It has been reported that YAP is highly expressed in human GC tumors, but the role of YAP in normal ovarian follicle development is largely unknown. In current study, we examined YAP expression in bovine ovaries. We demonstrate that downstream hippo signaling effector protein, YAP and transcription co-activator, TAZ, are present and localization of both YAP and TAZ are density-dependent. Likewise, YAP and TAZ are critically involved in granulosa cell proliferation. Furthermore, reducing YAP in granulosa cells inhibits FSH-induced aromatase expression and estradiol biosynthesis. The data suggest that YAP plays an important role in the development of ovarian follicles and estradiol synthesis, which are necessary for maintaining normal ovarian function.

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Expression of microRNAs and their target genes and pathways associated with ovarian follicle development in cattle

Physiological Genomics ◽

10.1152/physiolgenomics.00036.2014 ◽

2014 ◽

Vol 46 (19) ◽

pp. 735-745 ◽

Cited By ~ 19

Author(s):

A. E. Zielak-Steciwko ◽

J. A. Browne ◽

P. A. McGettigan ◽

M. Gajewska ◽

M. Dzięcioł ◽

...

Keyword(s):

Granulosa Cells ◽

Target Genes ◽

Ovarian Follicle ◽

Target Prediction ◽

Mapk Signaling ◽

Differentially Expressed ◽

Follicle Development ◽

Messenger Rnas ◽

Ovarian Follicle Development ◽

Differentially Expressed Mirnas

Development of ovarian follicles is controlled at the molecular level by several gene products whose precise expression leads to regression or ovulation of follicles. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression through sequence-specific base pairing with target messenger RNAs (mRNAs) causing translation repression or mRNA degradation. The aim of this study was to identify miRNAs expressed in theca and/or granulosa layers and their putative target genes/pathways that are involved in bovine ovarian follicle development. By using miRCURY microarray (Exiqon) we identified 14 and 49 differentially expressed miRNAs ( P < 0.01) between dominant and subordinate follicles in theca and granulosa cells, respectively. The expression levels of four selected miRNAs were confirmed by qRT-PCR. To identify target prediction and pathways of differentially expressed miRNAs we used Union of Genes option in DIANA miRPath v.2.0 software. The predicted targets for these miRNAs were enriched for pathways involving oocyte meiosis, Wnt, TGF-beta, ErbB, insulin, P13K-Akt, and MAPK signaling pathways. This study identified differentially expressed miRNAs in the theca and granulosa cells of dominant and subordinate follicles and implicates them in having important roles in regulating known molecular pathways that determine the fate of ovarian follicle development.

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Bone morphogenetic protein 6 promotes FSH receptor and anti-Müllerian hormone mRNA expression in granulosa cells from hen prehierarchal follicles

Reproduction ◽

10.1530/rep-11-0271 ◽

2012 ◽

Vol 143 (6) ◽

pp. 825-833 ◽

Cited By ~ 38

Author(s):

O M Ocón-Grove ◽

D H Poole ◽

A L Johnson

Keyword(s):

Mrna Expression ◽

Bone Morphogenetic Proteins ◽

Granulosa Cells ◽

Ovarian Follicle ◽

Follicle Development ◽

Fsh Receptor ◽

Ovarian Follicle Development ◽

Morphogenetic Protein ◽

Preovulatory Follicles ◽

Initial Hypothesis

A growing body of literature provides evidence of a prominent role for bone morphogenetic proteins (BMPs) in regulating various stages of ovarian follicle development. Several actions for BMP6 have been previously reported in the hen ovary, yet only within postselection (preovulatory) follicles. The initial hypothesis tested herein is that BMP6 increases FSH receptor (FSHR) mRNA expression within the granulosa layer of prehierarchal (6–8 mm) follicles (6–8 GC). BMP6 mRNA is expressed at higher levels within undifferentiated (1–8 mm) follicles compared with selected (≥9 mm) follicles. Recombinant human (rh) BMP6 initiates SMAD1, 5, 8 signaling in cultured 6–8 GC and promotes FSHR mRNA expression in a dose-related fashion. In addition, a 21 h preculture with rhBMP6 followed by a 3 h challenge with FSH increases cAMP accumulation, STAR (StAR) expression, and progesterone production. Interestingly, rhBMP6 also increases expression of anti-Müllerian hormone (AMH) mRNA in cultured 6–8 GC. This related BMP family member has previously been implicated in negatively regulating FSH responsiveness during follicle development. Considering these data, we propose that among the paracrine and/or autocrine actions of BMP6 within prehierarchal follicles is the maintenance of both FSHR and AMH mRNA expression. We predict that before follicle selection, one action of AMH within granulosa cells from 6 to 8 mm follicles is to help suppress FSHR signaling and prevent premature granulosa cell differentiation. At the time of selection, we speculate that the yet undefined signal directly responsible for selection initiates FSH responsiveness. As a result, FSH signaling suppresses AMH expression and initiates the differentiation of granulosa within the selected follicle.

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PRMT5 regulates ovarian follicle development by facilitating Wt1 translation

10.1101/2021.04.04.438394 ◽

2021 ◽

Author(s):

Min Chen ◽

Fangfang Dong ◽

Min Chen ◽

Zhiming Shen ◽

Haowei Wu ◽

...

Keyword(s):

Granulosa Cell ◽

Granulosa Cells ◽

Ovarian Follicle ◽

Cell Lineage ◽

Arginine Methylation ◽

Major Type ◽

Follicle Development ◽

Ovarian Follicle Development ◽

High Level

AbstractProtein arginine methyltransferase 5 (Prmt5) is the major type II enzyme responsible for symmetric dimethylation of arginine. Here, we found PRMT5 was expressed at high level in ovarian granulosa cells of growing follicles. Inactivation of Prmt5 in granulosa cells resulted in aberrant follicle development and female infertility. In Prmt5-knockout mice, follicle development was arrested with disorganized granulosa cells in which WT1 expression was dramatically reduced and the expression of steroidogenesis-related genes was significantly increased. The premature differentiated granulosa cells were detached from oocytes and follicle structure was disrupted. Mechanism studies revealed that Wt1 expression was regulated by PRMT5 at the protein level. PRMT5 facilitated IRES-dependent translation of Wt1 mRNA by methylating HnRNPA1. Moreover, the upregulation of steroidogenic genes in Prmt5-deficient granulosa cells was repressed by Wt1 overexpression. These results demonstrate PRMT5 participates in granulosa cell lineage maintenance by inducing Wt1 expression. Our study uncovers a new role of post-translational arginine methylation in granulosa cell differentiation and follicle development.

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Notch Signaling Is Involved in Ovarian Follicle Development by Regulating Granulosa Cell Proliferation

Endocrinology ◽

10.1210/en.2010-1182 ◽

2011 ◽

Vol 152 (6) ◽

pp. 2437-2447 ◽

Cited By ~ 60

Author(s):

Chun-Ping Zhang ◽

Jun-Ling Yang ◽

Jun Zhang ◽

Lei Li ◽

Lin Huang ◽

...

Keyword(s):

Cell Proliferation ◽

Notch Signaling ◽

Granulosa Cell ◽

Granulosa Cells ◽

Ovarian Follicle ◽

Butyl Ester ◽

Follicular Development ◽

Follicle Development ◽

Ovarian Follicle Development

Notch signaling is an evolutionarily conserved pathway, which regulates cell proliferation, differentiation, and apoptosis. It has been reported that the members of Notch signaling are expressed in mammalian ovaries, but the exact functions of this pathway in follicle development is still unclear. In this study, primary follicles were cultured in vitro and treated with Notch signaling inhibitors, L-658,458 and N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT). We found that the cultured follicles completely stopped developing after L-658,458 and DAPT treatment, most of the granulosa cells were detached, and the oocytes were also degenerated with condensed cytoplasma. Further studies demonstrated that the proliferation of granulosa cells was dependent on the Notch signaling. L-658,458 and DAPT treatment inhibited proliferation of in vitro cultured primary granulosa cells and decreased the expression of c-Myc. Lentivirus mediated overexpression of Notch intracellular domain 2, and c-Myc could promote the proliferation of granulosa cells and rescue the growth inhibition induced by L-658,458 and DAPT. In conclusion, Notch signaling is involved in follicular development by regulating granulosa cell proliferation.

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Cellular basis for paracrine regulation of ovarian follicle development

Reproduction ◽

10.1530/rep.0.1210647 ◽

2001 ◽

pp. 647-653 ◽

Cited By ~ 310

Author(s):

DF Albertini ◽

CM Combelles ◽

E Benecchi ◽

MJ Carabatsos

Keyword(s):

Granulosa Cells ◽

Assisted Reproductive Technologies ◽

Developmental Regulation ◽

Ovarian Follicle ◽

Somatic Cells ◽

Reproductive Technologies ◽

Follicle Development ◽

Paracrine Factors ◽

Primordial Follicles ◽

Ovarian Follicle Development

Paracrine factors secreted by oocytes and somatic cells regulate many important aspects of early ovarian follicle development in mammals. From activation of dormant primordial follicles to selection of secondary follicles, locally acting factors have been identified that appear to exert important effects on the growth and differentiation of oocytes and granulosa cells. This article summarizes evidence to support a model for bi-directional paracrine communication that is based on developmental regulation of the delivery and reception of paracrine factors at the oocyte-granulosa cell interface. Transzonal projections that originate from granulosa cells and terminate at the oocyte plasma membrane provide a polarized means to orient the secretory organelles of somatic cells. Characterization of transzonal projections in follicles from normal and genetically modified mice reveals dynamic changes in the density and stability of transzonal projections. On the basis of new data analysing the orientation and cytoskeletal content of transzonal projections in mammalian oocytes, a model is proposed for regulation of paracrine growth factor secretion by follicle-stimulating hormone. These findings have immediate implications for ovarian hyperstimulation protocols and follicle culture models as related to the production of mammalian embryos by assisted reproductive technologies.

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