Oocyte-secreted factros regulate granulosa cell steroidogenesis

Zygote ◽  
1996 ◽  
Vol 4 (04) ◽  
pp. 317-321 ◽  
Author(s):  
Barbara C. Vanderhyden
Keyword(s):  
Cell Proliferation ◽  
Germ Cell ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Follicular Fluid ◽  
Follicular Development ◽  
Inhibitory Factor ◽  
Preovulatory Follicles ◽  
Loss Of Contact

Investigations of strains of mice defective in germ cell development have revealed the importance of oocytes for the initial stages of folliculogenesis (Pellaset al., 1991; Huanget al., 1993). Various aspects of follicular development are dependent upon and/or influenced by the presence of oocytes, including granulosa cell proliferation (Vanderhydenet al., 1990, 1992) and cumulus expansion (Buccioneet al., 1990; Salustriet al., 1990; Vanderhydenet al., 1990; Vanderhyden, 1993). We are investigating the possibility that oocytes influence one of the primary functions of granulosa cells: steroidogenesis. In many species, granulosa cells removed from preovulatory follicles luteinisein vitro(Channinget al., 1982), presumably due to loss of contact with follicular luteinisation inhibitory factor(s). Indeed, follicular fluid can prevent granulosa cell luteinisationin vitro(Ledwitz-Rigbyet al., 1977). Follicular fluid, however, may simply be the medium for transport of factors secreted by oocytes to regulate granulosa cell activities.

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

Endocrinology ◽  
2011 ◽  
Vol 152 (6) ◽  
pp. 2437-2447 ◽  
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.

scholarly journals AKT is involved in granulosa cell autophagy regulation via mTOR signaling during rat follicular development and atresia

Reproduction ◽  
2014 ◽  
Vol 147 (1) ◽  
pp. 73-80 ◽  
Author(s):  
JongYeob Choi ◽  
MinWha Jo ◽  
EunYoung Lee ◽  
DooSeok Choi
Keyword(s):  
Cell Death ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Apoptotic Cell ◽  
Follicular Development ◽  
Negative Regulator ◽  
Metabolic Clearance ◽  
Akt Inhibitor ◽  
Western Blots

In this study, we examined whether granulosa cell autophagy during follicular development and atresia was regulated by the class I phosphoinositide-3 kinase/protein kinase B (AKT) pathway, which is known to control the activity of mammalian target of rapamycin (mTOR), a major negative regulator of autophagy. Ovaries and granulosa cells were obtained using an established gonadotropin-primed immature rat model that induces follicular development and atresia. Autophagy was evaluated by measuring the expression level of microtubule-associated protein light chain 3-II (LC3-II) using western blots and immunohistochemistry. The activity of AKT and mTOR was also examined by observing the phosphorylation of AKT and ribosomal protein S6 kinase (S6K) respectively. After gonadotropin injection, LC3-II expression was suppressed and phosphorylation of AKT and S6K increased in rat granulosa cells. By contrast, gonadotropin withdrawal by metabolic clearance promoted LC3-II expression and decreased phosphorylation of AKT and S6K. In addition,in-vitroFSH treatment of rat granulosa cells also indicated inhibition of LC3-II expression accompanied by a marked increase in phosphorylation of AKT and S6K. Inhibition of AKT phosphorylation using AKT inhibitor VIII suppressed FSH-mediated phosphorylation of S6K, followed by an increase in LC3-II expression. Furthermore, co-treatment with FSH and AKT inhibitor increased the levels of apoptosis and cell death of granulosa cells compared with the single treatment with FSH. Taken together, our findings indicated that AKT-mediated activation of mTOR suppresses granulosa cell autophagy during follicular development and is involved in the regulation of apoptotic cell death.

scholarly journals The Phytoestrogen Quercetin Impairs Steroidogenesis and Angiogenesis in Swine Granulosa Cells In Vitro

2009 ◽  
Vol 2009 ◽  
pp. 1-8 ◽  
Author(s):  
Sujen Eleonora Santini ◽  
Giuseppina Basini ◽  
Simona Bussolati ◽  
Francesca Grasselli
Keyword(s):  
Granulosa Cell ◽  
Granulosa Cells ◽  
Follicular Development ◽  
Redox Status ◽  
Negative Influence ◽  
Animal Nutrition ◽  
Follicle Development ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Experimental evidence documents that nutritional phytoestrogens may interact with reproductive functions but the exact mechanism of action is still controversial. Since quercetin is one of the main flavonoids in livestock nutrition, we evaluated its possible effects on cultured swine granulosa cell proliferation, steroidogenesis, and redox status. Moreover, since angiogenesis is essential for follicle development, the effect of the flavonoid on Vascular Endothelial Growth Factor output by granulosa cells was also taken into account. Our data evidence that quercetin does not affect granulosa cell growth while it inhibits progesterone production and modifies estradiol production in a dose-related manner. Additionally, the flavonoid interferes with the angiogenic process by inhibiting VEGF production as well as by altering redox status. Since steroidogenesis and angiogenesis are strictly involved in follicular development, these findings appear particularly relevant, pointing out a possible negative influence of quercetin on ovarian physiology. Therefore, the possible reproductive impact of the flavonoid should be carefully considered in animal nutrition.

Inhibition of pig granulosa cell adhesion and growth in vitro by immunoneutralization of epithelial cadherin

Reproduction ◽  
2000 ◽  
pp. 275-281 ◽  
Author(s):  
KM Kirkup ◽  
AM Mallin ◽  
CA Bagnell
Keyword(s):  
Cell Proliferation ◽  
Cell Adhesion ◽  
Dna Synthesis ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Cell Contact ◽  
Mouse Ascites ◽  
Proliferation In Vitro ◽  
E Cadherin

Epithelial cadherin (E-cadherin) is a member of the cadherin family of calcium-dependent cell adhesion molecules and is present in the ovary. Although expression of E-cadherin is high in healthy pig granulosa cells and low in granulosa cells of atretic follicles, the importance of E-cadherin-mediated adhesion in granulosa cell function is unclear. The aim of the present study was to determine the impact of immunoneutralization of E-cadherin on granulosa cell adhesion, DNA synthesis and cell proliferation in vitro. Before attachment, pig granulosa cells were exposed to a monoclonal E-cadherin antibody (DECMA-1) which blocks E-cadherin function. Controls included substitution of the antibody with either mouse ascites fluid or another E-cadherin antibody directed against the cytoplasmic domain and which was therefore inaccessible in intact cells. Both granulosa cell proliferation and insulin-like growth factor I-induced DNA synthesis were inhibited significantly in the presence of DECMA-1 compared with controls (P < 0.05). Control granulosa cells in culture formed large clusters with many cells packed tightly together. However, after 48 h exposure to the function-perturbing E-cadherin antibody, there was a significant decrease in the size of the granulosa cell clusters (P < 0.05) and the degree of cell-cell contact was reduced compared with control cultures. No effects on DNA synthesis, cell proliferation or cell adhesion were observed when DECMA-1 was substituted with either mouse ascites fluid or the antibody specific for the cytoplasmic domain of E-cadherin. In conclusion, these data provide evidence to support the hypothesis that E-cadherin is important for maintaining granulosa cell contact, DNA synthesis and cell proliferation in vitro. These results indicate that E-cadherin plays a fundamental role in maintaining both the structure and function of ovarian follicles.

scholarly journals The conflict between hierarchical ovarian follicular development and superovulation treatment

Reproduction ◽  
2010 ◽  
Vol 140 (2) ◽  
pp. 287-294 ◽  
Author(s):  
Kenneth P McNatty ◽  
Derek A Heath ◽  
Norma L Hudson ◽  
Karen L Reader ◽  
Laurel Quirke ◽  
...  
Keyword(s):  
Granulosa Cell ◽  
Granulosa Cells ◽  
Follicular Development ◽  
Follicular Phase ◽  
Ovulation Rate ◽  
Cell Populations ◽  
Antral Follicles ◽  
Functional States ◽  
Ovarian Follicular Development

In mammals with a low ovulation rate phenotype, ovarian follicular development is thought to be hierarchical with few, if any, antral follicles at similar stages of development. The hypothesis being tested herein was that if most follicles are in a functionally different state, then the application of exogenous hormones to increase ovulation rate will not overcome the hierarchical nature of follicular development. Using sheep as the experimental model, the functional states of all non-atretic antral follicles ≥2 mm diameter were assessed in individual ewes (N=10/group) during anoestrus with or without pregnant mare's serum gonadotrophin (PMSG) treatment, or after a standard superovulation regimen, or during the follicular phase of the oestrous cycle. The functional states of these follicles were assessed by measuring the FSH- or human chorionic gonadotrophin (hCG)-induced cAMP responses of granulosa cellsin vitro. There were significant overall effects across the treatment groups on the responses of granulosa cells to either FSH or LH (bothP<0.001). It was concluded that for anoestrous ewes with or without PMSG treatment, and ewes during the follicular phase, granulosa cell populations of many follicles (≥2 mm diameter) did not share a similar cAMP response to FSH (∼50% of follicles) or hCG (>90% of follicles) either on a per cell or total cell basis. After superovulation, ≤30 and 10% respectively of the granulosa cell populations shared similar responses to FSH and LH with regard to follicular diameter and cAMP output. Thus, exogenous hormone treatments used routinely for increasing oocyte yield do not effectively override the hierarchical pattern of ovarian follicular development during the follicular phase.

Exosomal miR-143-3p Derived from PCOS Follicular Fluid Induces Granulosa Cell Apoptosis by Targeting BMPR1A and Suppression of Smad1/5/8 Signaling

2021 ◽  
Author(s):  
Yuanyuan Zhao ◽  
Shuhong Pan ◽  
Yunying Li ◽  
Xiaohua Wu
Keyword(s):  
Signaling Pathway ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Follicular Fluid ◽  
Cell Apoptosis ◽  
Polycystic Ovary ◽  
Follicular Development ◽  
Reproductive Age ◽  
Exosomal Mirnas ◽  
Exosomal Mirna

Abstract Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorders disease in women of reproductive age. The anovulation caused by abnormal follicular development is still the main characteristic of infertile patients with PCOS. Granulosa cells (GCs), an important component of follicular microenvironment, affect follicular development through GCs dysfunction. Increasing evidence indicates that exosomal miRNAs derived from follicular fluid (FF) of patients play critical roles during PCOS. However, which and how follicular fluid derived exosomal miRNAs play a pivotal role in controlling granulosa cells function and consequently follicular development remain largely unknown. Herein, we showed that miR-143-3p is highly expressed in follicular fluid exosomes of PCOS patients and can be delivered into granulosa cells. Furthermore, the functional experiments showed that the translocated miR-143-3p promoted granulosa cell apoptosis, which are important in follicle development. In terms of mechanism, we demonstrated that BMPR1A was identified as a direct target of miR-143-3p. Overexpression of BMPR1A reversed the effects of exosomal miR-143-3p on GCs apoptosis and proliferation by activating Smad1/5/8 signaling pathway. These results demonstrate that miR-143-3p-containing exosomes derived from PCOS follicular fluid promoted granulosa cell apoptosis by targeting BMPR1A and blockading Smad1/5/8 signaling pathway. Our findings provide a novel mechanism underlying the roles of exosomal-miRNA in follicular fluid of PCOS and facilitate the development of therapeutic strategies for PCOS.

Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes

Development ◽  
2000 ◽  
Vol 127 (19) ◽  
pp. 4277-4291 ◽  
Author(s):  
S. Dupont ◽  
A. Krust ◽  
A. Gansmuller ◽  
A. Dierich ◽  
P. Chambon ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Estrogen Receptors ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Glandular Cell ◽  
Wild Type ◽  
Mouse Ovary ◽  
Preovulatory Follicles ◽  
Cell Layers ◽  
Ovarian Folliculogenesis

The functions of estrogen receptors (ERs) in mouse ovary and genital tracts were investigated by generating null mutants for ERalpha (ERalphaKO), ERbeta (ERbetaKO) and both ERs (ERalphabetaKO). All ERalphaKO females are sterile, whereas ERbetaKO females are either infertile or exhibit variable degrees of subfertility. Mast cells present in adult ERalphaKO and ERalphabetaKO ovaries could participate in the generation of hemorrhagic cysts. Folliculogenesis proceeds normally up to the large antral stage in both ERalphaKO and ERbetaKO adults, whereas large antral follicles of ERalpha+/−ERbetaKO and ERalphabetaKO adults are markedly deficient in granulosa cells. Similarly, prematurely developed follicles found in prepubertal ERalphaKO ovaries appear normal, but their ERalphabetaKO counterparts display only few granulosa cell layers. Upon superovulation treatment, all prepubertal ERalphaKO females form numerous preovulatory follicles of which the vast majority do not ovulate. The same treatment fails to elicit the formation of preovulatory follicles in half of the ERbetaKO mice and in all ERalpha+/−/ERbetaKO mice. These and other results reveal a functional redundancy between ERalpha and ERbeta for ovarian folliculogenesis, and strongly suggest that (1) ERbeta plays an important role in mediating the stimulatory effects of estrogens on granulosa cell proliferation, (2) ERalpha is not required for follicle growth under wild type conditions, while it is indispensable for ovulation, and (3) ERalpha is also necessary for interstitial glandular cell development. Our data also indicate that ERbeta exerts some function in ERalphaKO uterus and vagina. ERalphabetaKO granulosa cells localized within degenerating follicles transform into cells displaying junctions that are unique to testicular Sertoli cells. From the distribution pattern of anti-Mullerian hormone (AMH) in ERalphabetaKO ovaries, it is unlikely that an elevated AMH level is the cause of Sertoli cell differentiation. Our results also show that cell proliferation in the prostate and urinary bladder of old ERbetaKO and ERalphabetaKO males is apparently normal.

Control of inhibin production by primate granulosa cells

1989 ◽  
Vol 123 (1) ◽  
pp. 65-73 ◽  
Author(s):  
S. G. Hillier ◽  
E. J. Wickings ◽  
P. T. K. Saunders ◽  
A. F. Dixson ◽  
S. Shimasaki ◽  
...  
Keyword(s):  
Granulosa Cell ◽  
Granulosa Cells ◽  
Follicular Development ◽  
Common Marmoset ◽  
Dependent Manner ◽  
Stimulatory Action ◽  
Α Subunit ◽  
Luteal Tissue ◽  
Ovarian Inhibin

ABSTRACT In-vitro data from experiments on rats implicate granulosa cells as primary sites of hormone-dependent ovarian inhibin biosynthesis, but no equivalent data exist for primates. We have used the common marmoset (Callithrix jacchus) to investigate inhibin biosynthesis in primate granulosa cells in vitro and to determine its relationship to preovulatory follicular development. To relate the production of immunoactive inhibin to follicular maturity, we studied primary granulosa cell cultures from follicles at progressive stages of preovulatory development. Granulosa cells from 'large' (≥2·0 mm diameter) follicles expressed high rates of inhibin production and steroidogenesis (progesterone), and were positively regulated by human (h)LH in vitro. Less mature granulosa cells from 'medium' (1·1–1·9 mm) and 'small' (≤ 1·0 mm) follicles expressed proportionately lower rates of inhibin production and steroidogenesis, but each parameter was stimulated in a dose- and time-dependent manner by hFSH in vitro. The stimulatory action of hFSH on immunoactive inhibin was augmented by the presence of testosterone or oestradiol; testosterone (but not oestradiol) also augmented the steroidogenic response to hFSH. Marmoset luteal tissue also produced inhibin in vitro and expressed an ∼1·5 kb inhibin α-subunit mRNA, confirming the corpus luteum as a source of ovarian inhibin in primates. These results provide direct experimental evidence that primate granulosa cells produce inhibin. They suggest that production of inhibin by immature granulosa cells is initially induced by FSH and subject to modulation by follicular steroids. During advanced preovulatory development, granulosa cell inhibin production becomes directly responsive to LH, thereby indicating a role for LH in the control of peri- and postovulatory inhibin secretion by the primate ovary. Journal of Endocrinology (1989) 123, 65–73

Effect of hypothyroidism on ovarian follicular development, granulosa cell proliferation and peripheral hormone levels in the prepubertal rat

1996 ◽  
Vol 134 (5) ◽  
pp. 649-654 ◽  
Author(s):  
Grietje Dijkstra ◽  
Dirk G de Rooij ◽  
Frank H de Jong ◽  
Robert van den Hurk
Keyword(s):  
Cell Proliferation ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Ovarian Development ◽  
Follicular Development ◽  
Corpora Lutea ◽  
Hormone Levels ◽  
Antral Follicles ◽  
Ovarian Follicular Development ◽  
Serum Tsh

Dijkstra G, de Rooij DG, de Jong FH, van den Hurk R. Effect of hypothyroidism on ovarian follicular development, granulosa cell proliferation and peripheral hormone levels in the prepubertal rat. Eur J Endocrinol 1996;134:649–54. ISSN 0804–4643 The aim of this study was to examine the effects of prepubertal hypothyroidism on ovarian development in rats. Therefore, from birth up to day 40 postpartum, rats were given 6-propyl-2-thiouracil (PTU) via the drinking water of mothers and pups. At ages ranging from 12 to 40 days, ovarian weights were measured and serum was collected to estimate thyrotrophin (TSH), folliclestimulating hormone (FSH) and inhibin levels. Two hours before sacrifice the animals received an injection of bromodeoxyuridine (BrdU) to estimate the proliferative activity of the follicular granulosa cells. Ovaries were fixed in Carnoy's fluid and follicle counts were performed on sections stained with anti-BrdU and with haematoxylin and eosin. The PTU treatment resulted in increased serum TSH levels, indicative of hypothyroidism, and markedly lower body and ovarian weights, whereas serum FSH and inhibin levels were hardly affected. At day 40, ovaries of PTU-treated animals contained relatively more secondary and less antral follicles, smaller non-atretic antral follicles and more atretic follicles when compared with untreated rats, while corpora lutea were absent. It is concluded that this disturbed folliculogenesis is due to inadequate thyroid hormone supply, which hampers the differentiation and not the proliferation of granulosa cells because diameters of antral follicles were significantly smaller whereas the BrdU-labelling index had not changed. Robert van den Hurk, Department of Functional Morphology, Faculty of Veterinary Medicine, PO Box 80.157, 3508 TD Utrecht, The Netherlands

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