509. REGULATING MURINE FOLLICLE DEVELOPMENT BY STIMULATION OF THE JAK2/STAT3 SIGNAL TRANSDUCTION PATHWAY

2009 ◽  
Vol 21 (9) ◽  
pp. 108
Author(s):  
R. A. Keightley ◽  
B. Nixon ◽  
S. D. Roman ◽  
D. L. Russell ◽  
R. L. Robker ◽  
...  
Keyword(s):  
Significant Role ◽  
Granulosa Cells ◽  
Ovarian Follicle ◽  
Expression Patterns ◽  
Follicular Development ◽  
Janus Kinase ◽  
Follicle Development ◽  
Mrna Levels ◽  
Primordial Follicles ◽  
Stat3 Signalling

Follicular development requires the recruitment of primordial follicles into the growing follicle pool following initiation of multiple cytokine signalling pathways. Suppression of follicular development is thought to be key to maintaining the population of primordial follicles and allowing for controlled release of these follicles throughout the reproductive lifespan of the female. However, little is known of the processes and signalling molecules that suppress primordial follicle activation and early follicle growth. Our group has identified significant upregulation of the Janus Kinase 2 (JAK2)/ Signal Transducer and Activator of Transcription 3 (STAT3) signalling pathway inhibitor the Suppressor of Cytokine Signalling 4 (SOCS4) that coincides with the initial wave of follicular activation in theneonatal mouse ovary. Further studies by our group have localised the SOCS4 protein to the granulosa cells of activating and growing follicles, suggesting SOCS4 expression may be linked to follicular activation. We have focused on examining protein localisation and gene expression patterns of the eight SOCS family members CIS and SOCS1-7. We have recently demonstrated that co-culture of neonatal ovaries with Kit Ligand (KL) for 2 days increases the mRNA levels of all SOCS genes. We also demonstrated the co-localisation of SOCS2 proteins with the KL receptor c-kit in the mural granulosa cells of antral, and large pre-antral follicles suggesting a significant role for SOCS2 in the later stages of follicular development. We have also shown that culturing ovaries with the potent JAK2 inhibitor AG490 substantially reduces mRNA levels of all SOCS and STAT genes that we have so far measured. We hypothesise a significant role for JAK2/STAT3 signalling in promoting the activation and early growth of ovarian follicles. Our investigations have identified significant roles for JAK2/STAT3 and the SOCS family in the regulation of ovarian follicle development.

268. Suppressors of cytokine signalling (SOCS): roles in ovarian follicle activation

2008 ◽  
Vol 20 (9) ◽  
pp. 68
Author(s):  
R. Keightley ◽  
E. McLaughlin ◽  
S. D. Roman ◽  
R. L. Robker ◽  
D. L. Russell
Keyword(s):  
Granulosa Cells ◽  
Ovarian Follicle ◽  
Expression Patterns ◽  
Neonatal Mouse ◽  
Mrna Levels ◽  
Follicle Growth ◽  
Oocyte Growth ◽  
Primordial Follicles ◽  
Gene And Protein Expression ◽  
Follicle Activation

Oocytes are sequestered in primordial follicles before birth and remain quiescent in the ovary for decades, until recruited into the growing pool throughout the reproductive years. Therefore activation of follicle growth is a major biological checkpoint that controls female reproductive potential. However we are only just beginning to elucidate the cellular mechanisms required, for either maintenance of the quiescent primordial pool, or initiation of follicle growth. Analysis of microarray data derived from neonatal mouse ovaries indicated that members of the Suppressors of Cytokine Signalling SOCS family of proteins may play pivotal roles in folliculogenesis. We undertook a detailed analysis of gene and protein expression patterns of the eight members of the SOCS family, namely CIS and SOCS1–7, within adult and neonatal mouse ovaries. Quantitative real time PCR and immunohistochemistry was performed to determine mRNA levels and cellular localisation in the ovaries of cycling and new born animals. SOCS proteins were expressed largely within the oocytes of developing follicles and in the granulosa cells of the larger preovulatory follicles. Expression of SOCS4 in the granulosa cells and SOCS5 within the oocyte was coincident with the activation of oocyte growth and the differentiation of squamous pregranulosa to cuboidal granulosa cells. Our investigation has identified a role for the SOCS family proteins within the ovary and SOCS4 and SOCS5 as major regulators of cytokine signalling pathways in follicle activation and development.

scholarly journals Cytokine (IL16) and tyrphostin actions on ovarian primordial follicle development

Reproduction ◽  
2014 ◽  
Vol 148 (3) ◽  
pp. 321-331 ◽  
Author(s):  
Amanda Feeney ◽  
Eric Nilsson ◽  
Michael K Skinner
Keyword(s):  
Signaling Pathways ◽  
Signaling Pathway ◽  
Granulosa Cells ◽  
Ovarian Follicle ◽  
Primordial Follicle ◽  
Cytokine Signaling ◽  
Follicle Development ◽  
Primary Follicle ◽  
Primordial Follicles ◽  
Network Analyses

An ovarian follicle is composed of an oocyte and surrounding theca and granulosa cells. Oocytes are stored in an arrested state within primordial follicles until they are signaled to re-initiate development by undergoing primordial-to-primary follicle transition. Previous gene bionetwork analyses of primordial follicle development identified a number of critical cytokine signaling pathways and genes potentially involved in the process. In the current study, candidate regulatory genes and pathways from the gene network analyses were tested for their effects on the formation of primordial follicles (follicle assembly) and on primordial follicle transition using whole ovary organ culture experiments. Observations indicate that the tyrphostin inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one increased follicle assembly significantly, supporting a role for the MAPK signaling pathway in follicle assembly. The cytokine interleukin 16 (IL16) promotes primordial-to-primary follicle transition as compared with the controls, where as Delta-like ligand 4 (DLL4) and WNT-3A treatments have no effect. Immunohistochemical experiments demonstrated the localization of both the cytokine IL16 and its receptor CD4 in the granulosa cells surrounding each oocyte within the ovarian follicle. The tyrphostin LDN193189 (LDN) is an inhibitor of the bone morphogenic protein receptor 1 within the TGFB signaling pathway and was found to promote the primordial-to-primary follicle transition. Observations support the importance of cytokines (i.e., IL16) and cytokine signaling pathways in the regulation of early follicle development. Insights into regulatory factors affecting early primordial follicle development are provided that may associate with ovarian disease and translate to improved therapy in the future.

scholarly journals Photoperiod-dependent modulation of anti-Müllerian hormone in female Siberian hamsters, Phodopus sungorus

Reproduction ◽  
2008 ◽  
Vol 135 (3) ◽  
pp. 335-342 ◽  
Author(s):  
Esther W Kabithe ◽  
Ned J Place
Keyword(s):  
Granulosa Cells ◽  
Expression Patterns ◽  
Follicular Development ◽  
Day Length ◽  
Phodopus Sungorus ◽  
Reproductive Aging ◽  
Primordial Follicles ◽  
Short Day ◽  
Siberian Hamsters ◽  
Secondary Stage

Fertility and fecundity decline with advancing age in female mammals, but reproductive aging was decelerated in Siberian hamsters (Phodopus sungorus) raised in a short-day (SD) photoperiod. Litter success was significantly improved in older hamsters when reared in SD and the number of primordial follicles was twice that of females held in long days (LD). Because anti-Müllerian hormone (AMH) appears to inhibit the recruitment of primordial follicles in mice, we sought to determine whether the expression patterns of AMH differ in the ovaries and serum of hamsters raised in SD versus LD. Ovaries of SD female hamsters are characterized by a paucity of follicular development beyond the secondary stage and are endowed with an abundance of large eosinophilic cells, which may derive from granulosa cells of oocyte-depleted follicles. In ovaries from 10-week-old SD hamsters, we found that the so-called ‘hypertrophied granulosa cells’ were immunoreactive for AMH, as were granulosa cells within healthy-appearing primary and secondary follicles. Conversely, ovaries from age-matched LD animals lack the highly eosinophilic cells present in SD ovaries. Therefore, AMH staining in LD was limited to primary and secondary follicles that are comparable in number to those found in SD ovaries. The substantially greater AMH expression in SD ovaries probably reflects the abundance of hypertrophied granulosa cells in SD ovaries and their relative absence in LD ovaries. The modulation of ovarian AMH by day length is a strong mechanistic candidate for the preservation of primordial follicles in female hamsters raised in a SD photoperiod.

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 Cellular basis for paracrine regulation of ovarian follicle development

Reproduction ◽  
2001 ◽  
pp. 647-653 ◽  
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.

scholarly journals MicroRNA Mediating Networks in Granulosa Cells Associated with Ovarian Follicular Development

2017 ◽  
Vol 2017 ◽  
pp. 1-18 ◽  
Author(s):  
Baoyun Zhang ◽  
Long Chen ◽  
Guangde Feng ◽  
Wei Xiang ◽  
Ke Zhang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Granulosa Cells ◽  
Messenger Rna ◽  
Expression Patterns ◽  
Follicular Development ◽  
Functional Networks ◽  
Signal Pathways ◽  
Differentially Expressed Mirnas ◽  
Selection Of

Ovaries, which provide a place for follicular development and oocyte maturation, are important organs in female mammals. Follicular development is complicated physiological progress mediated by various regulatory factors including microRNAs (miRNAs). To demonstrate the role of miRNAs in follicular development, this study analyzed the expression patterns of miRNAs in granulosa cells through investigating three previous datasets generated by Illumina miRNA deep sequencing. Furthermore, via bioinformatic analyses, we dissected the associated functional networks of the observed significant miRNAs, in terms of interacting with signal pathways and transcription factors. During the growth and selection of dominant follicles, 15 dysregulated miRNAs and 139 associated pathways were screened out. In comparison of different styles of follicles, 7 commonly abundant miRNAs and 195 pathways, as well as 10 differentially expressed miRNAs and 117 pathways in dominant follicles in comparison with subordinate follicles, were collected. Furthermore, SMAD2 was identified as a hub factor in regulating follicular development. The regulation of miR-26a/b onsmad2messenger RNA has been further testified by real time PCR. In conclusion, we established functional networks which play critical roles in follicular development including pivotal miRNAs, pathways, and transcription factors, which contributed to the further investigation about miRNAs associated with mammalian follicular development.

scholarly journals An epigenetic switch repressingTet1in gonadotropes activates the reproductive axis

2017 ◽  
Vol 114 (38) ◽  
pp. 10131-10136 ◽  
Author(s):  
Yahav Yosefzon ◽  
Cfir David ◽  
Anna Tsukerman ◽  
Lilach Pnueli ◽  
Sen Qiao ◽  
...  
Keyword(s):  
Ovarian Function ◽  
Ovarian Follicle ◽  
Gene Promoter ◽  
Follicle Development ◽  
Mrna Levels ◽  
Epigenetic Switch ◽  
Ovarian Follicle Development ◽  
Reproductive Axis ◽  
Poorly Differentiated ◽  
Tet Enzymes

The TET enzymes catalyze conversion of 5-methyl cytosine (5mC) to 5-hydroxymethyl cytosine (5hmC) and play important roles during development. TET1 has been particularly well-studied in pluripotent stem cells, butTet1-KO mice are viable, and the most marked defect is abnormal ovarian follicle development, resulting in impaired fertility. We hypothesized that TET1 might play a role in the central control of reproduction by regulating expression of the gonadotropin hormones, which are responsible for follicle development and maturation and ovarian function. We find that all three TET enzymes are expressed in gonadotrope-precursor cells, butTet1mRNA levels decrease markedly with completion of cell differentiation, corresponding with an increase in expression of the luteinizing hormone gene,Lhb. We demonstrate that poorly differentiated gonadotropes express a TET1 isoform lacking the N-terminal CXXC-domain, which repressesLhbgene expression directly and does not catalyze 5hmC at the gene promoter. We show that this isoform is also expressed in other differentiated tissues, and that it is regulated by an alternative promoter whose activity is repressed by the liganded estrogen and androgen receptors, and by the hypothalamic gonadotropin-releasing hormone through activation of PKA. Its expression is also regulated by DNA methylation, including at an upstream enhancer that is protected by TET2, to allowTet1expression. The down-regulation of TET1 relieves its repression of the methylatedLhbgene promoter, which is then hydroxymethylated and activated by TET2 for full reproductive competence.

scholarly journals Heat stress diminishes gonadotropin receptor expression and enhances susceptibility to apoptosis of rat granulosa cells

Reproduction ◽  
2005 ◽  
Vol 129 (4) ◽  
pp. 463-472 ◽  
Author(s):  
Takashi Shimizu ◽  
Izumi Ohshima ◽  
Manabu Ozawa ◽  
Satoko Takahashi ◽  
Atsushi Tajima ◽  
...  
Keyword(s):  
Heat Stress ◽  
Granulosa Cells ◽  
Follicular Fluid ◽  
Follicular Development ◽  
Receptor Expression ◽  
Female Rats ◽  
Aromatase Activity ◽  
Mrna Levels ◽  
Gonadotropin Receptor ◽  
Estradiol Levels

Heat stress inhibits ovarian follicular development in mammalian species. We hypothesized that heat stress inhibits the function of follicular granulosa cells and suppresses follicular development. To test this, immature female rats were injected with pregnant mare serum gonadotropin (PMSG) at 48 h after the start of temperature treatment (control: 25 °C, 50% RH; heat stress: 35 °C, 70% Relative Humidity). The ovaries and granulosa cells of follicles at different developmental stages were analyzed for gonadotropin receptor levels and aromatase activity; estradiol levels were measured in follicular fluid. Before injection, heat stress diminished only the amount of FSH receptor on granulosa cells of antral follicles. During PMSG-stimulated follicular development, heat stress strongly inhibited gonadotropin receptor levels and aromatase activity in granulosa cells, and estradiol levels in the follicular fluid of early antral, antral and preovulatory follicles. To examine apoptosis and mRNA levels of bcl-2 and bax in granulosa cells, follicles harvested 48 h after PMSG injection were cultured in serum-free conditions. Heat-stressed granulosa cells showed a time-dependent increase in apoptosis. The bcl-2 mRNA levels were similar in control and heat-stressed granulosa cells; bax mRNA levels were increased in heat-stressed granulosa cells. According to these results, heat stress inhibits expression of gonadotropin receptors in granulosa cells and attenuates estrogenic activity of growing follicles, granulosa cells of heat-stressed follicles are susceptible to apoptosis, and the bcl2/bax system is not associated with heat-stress-induced apoptosis of granulosa cells. Our study suggests that decreased numbers and function of granulosa cells may cause ovarian dysfunction in domestic animals in summer.

scholarly journals Pentachloronitrobenzene alters progesterone production and primordial follicle recruitment in cultured granulosa cells and rat ovary†

2019 ◽  
Vol 102 (2) ◽  
pp. 511-520
Author(s):  
Yanrong Kuai ◽  
Xiaobo Gao ◽  
Huixia Yang ◽  
Haiyan Luo ◽  
Yang Xu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Granulosa Cells ◽  
Crop Production ◽  
Follicular Development ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Serum Progesterone ◽  
Primordial Follicles ◽  
Progesterone Production

Abstract Pentachloronitrobenzene (PCNB) is an organochlorine fungicide widely used for crop production and has become an environmental concern. Little is known about the effect of PCNB on ovarian steroidogenesis and follicular development. We found that PCNB stimulated Star expression and progesterone production in cultured rat granulosa cells in a dose-dependent manner. PCNB activated mitogen-activated protein kinase (MAPK3/1) extracellulat regulated kinase (ERK1/2), thus inhibition of either protein kinase A (PKA) or MAPK3/1 signaling pathway significantly attenuated progesterone biosynthesis caused by PCNB, suggesting that PCNB induced progesterone production by activating the cyclic adenosine monophosphate (cAMP/PKA) and MAPK3/1 signaling pathways. Further investigation demonstrated that PCNB induced Star expression and altered MAPK3/1 signaling in ovary tissues of immature SD rats treated with PCNB at the dose of 100, 200, or 300 mg/kg by daily gavage for 7 days, while serum progesterone level was dose-dependently decreased. We demonstrated that PCNB exposure accelerated the recruitment of primordial follicles into the growing follicle pool in ovary tissues, accompanied by increased levels of anti-Mullerian hormone (AMH) in both ovary tissues and serum. Taken together, our data demonstrate for the first time that PCNB stimulated Star expression, altered MAPK3/1 signaling and progesterone production in vivo and in vitro, and accelerated follicular development with a concomitant increase in AMH in ovary tissues and serum. Our findings provide novel insight into the toxicity of PCNB to animal ovary function.

scholarly journals Timely expression and activation of YAP1 in granulosa cells is essential for ovarian follicle development

2019 ◽  
Vol 33 (9) ◽  
pp. 10049-10064 ◽  
Author(s):  
Xiangmin Lv ◽  
Chunbo He ◽  
Cong Huang ◽  
Hongbo Wang ◽  
Guohua Hua ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Ovarian Follicle ◽  
Follicle Development ◽  
Ovarian Follicle Development
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