Transient Invasive Migration in Mouse Cumulus Oocyte Complexes Induced at Ovulation by Luteinizing Hormone1

Akison, Lisa K.; Alvino, E.; Dunning, Kylie R.; Robker, Rebecca L.; Russell, Darryl L.

doi:10.1095/biolreprod.111.097345

Cited by 43 publications

(26 citation statements)

References 73 publications

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“…Processes that are positively regulated include cellular movement, lipid metabolism, inflammatory response and immune cell trafficking. Akison et al (2012) has demonstrated that CCs in the expanded COC transition to an adhesive, motile and invasive phenotype in the periovulatory period similar to MB-231 invasive breast cancer cell line, which is in agreement with the increased cellular movement observed in CCM2 samples.…”

Section: Discussionsupporting

confidence: 76%

Characterization of the human cumulus cell transcriptome during final follicular maturation and ovulation

Yerushalmi

Salmon‐Divon

Yung

et al. 2014

MHR: Basic Science of Reproductive Medicine

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Cumulus expansion and oocyte maturation are central processes in ovulation. Knowledge gained from rodent and other mammalian models has revealed some of the molecular pathways associated with these processes. However, the equivalent pathways in humans have not been thoroughly studied and remain unidentified. Compact cumulus cells (CCs) from germinal vesicle cumulus oocyte complexes (COCs) were obtained from patients undergoing in vitro maturation (IVM) procedures. Expanded CCs from metaphase 2 COC were obtained from patients undergoing IVF/ICSI. Global transcriptome profiles of the samples were obtained using state-of-the-art RNA sequencing techniques. We identified 1746 differentially expressed (DE) genes between compact and expanded CCs. Most of these genes were involved in cellular growth and proliferation, cellular movement, cell cycle, cell-to-cell signaling and interaction, extracellular matrix and steroidogenesis. Out of the DE genes, we found 89 long noncoding RNAs, of which 12 are encoded within introns of genes known to be involved in granulosa cell processes. This suggests that unique noncoding RNA transcripts may contribute to the regulation of cumulus expansion and oocyte maturation. Using global transcriptome sequencing, we were able to generate a library of genes regulated during cumulus expansion and oocyte maturation processes. Analysis of these genes allowed us to identify important new genes and noncoding RNAs potentially involved in COC maturation and cumulus expansion. These results may increase our understanding of the process of oocyte maturation and could ultimately improve the efficacy of IVM treatment.

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Section: Discussionsupporting

confidence: 76%

Characterization of the human cumulus cell transcriptome during final follicular maturation and ovulation

Yerushalmi

Salmon‐Divon

Yung

et al. 2014

MHR: Basic Science of Reproductive Medicine

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“…However, currently, we cannot exclude the possibility that the inhibitory effect of both miR‐125a‐3p and Fyn siRNA on ovulation is not confined to mural granulosa cells. In that context, several studies pointed out the importance of migration of the cumulus cells in the process of cumulus expansion (37, 38). Because cumulus expansion is required for adequate ovulation (39), it is possible that over‐expression of miR‐125a‐3p and down‐regulation of Fyn may have interfered with cumulus migration, hampering its expansion and, hence, contributing to the inhibitory effect of miR‐125a‐3p and Fyn siRNA on ovulation in vivo.…”

Section: Discussionmentioning

confidence: 99%

A novel regulatory pathway in granulosa cells, the LH/human chorionic gonadotropin-microRNA-125a-3p-Fyn pathway, is required for ovulation

et al. 2015

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Granulosa cells support the developing oocytes and serve as transducers of the ovulatory stimulus induced by LH surge. Fyn kinase is expressed in granulosa cells, though its role in these cells has not been studied. In human embryonic kidney 293T cells, microRNA (miR)-125a-3p down-regulates Fyn expression, causing a decrease in cells' migratory ability. Our aim was to explore the role of miR-125a-3p and Fyn in granulosa cells toward ovulation, focusing on migration as a possible mechanism. We demonstrate expression of miR-125a-3p and Fyn in mouse mural granulosa cells of preovulatory follicles and miR125a-3p-induced down-regulation of Fyn expression in a granulosa cell line (rat). Administration of human chorionic gonadotropin (hCG; LH analog) caused a 75% decrease in the in vivo miR-125a-3p:Fyn mRNA ratio, followed by a 2-fold increased migratory ability of mural granulosa cells. In the hCG-treated granulosa cell line, miR-125a-3p expression was decreased, followed by Fyn up-regulation and phosphorylation of focal adhesion kinase and paxillin, enabling cell migration. An in vivo interference with miR125a-3p:Fyn mRNA ratio in granulosa cells by intrabursal injections of Fyn small interfering RNA or miR-125a-3p mimic caused a 33 or 55% decrease in the number of ovulated oocytes, respectively. These observations reveal a new regulatory pathway in mural granulosa cells under the regulation of LH/hCG. Modulation of cell migration may account for the significance of the LH/hCG-miR-125a-3p-Fyn pathway to ovulation.-Grossman, H., Chuderland, D., Ninio-Many, L., Hasky, N., Kaplan-Kraicer, R., Shalgi, R. A novel regulatory pathway in granulosa cells, the LH/human chorionic gonadotropin-microRNA-125a-3p-Fyn pathway, is required for ovulation. FASEB J. 29, 3206-3216 (2015). www.fasebj.org

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“…Betaglycan is a repressor of cell motility, and its down-regulation promotes motility in metastatic cancers (43). We recently reported that cumulus cells selectively acquire invasive motility during the periovulatory window (44) and this down-regulation of Betaglycan would be expected to facilitate this acquisition of motility in ovulating COC. Heparin treatment of COCs significantly increased Betaglycan expression which was reversed by GDF9 co-treatment providing the first evidence that Betaglycan mRNA is repressed in COC and this is GDF9 dependent.…”

Section: Discussionmentioning

confidence: 99%

Heparan Sulfate Proteoglycans Regulate Responses to Oocyte Paracrine Signals in Ovarian Follicle Morphogenesis

et al. 2012

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In the ovarian follicle, oocyte-secreted factors induce cumulus-specific genes and repress mural granulosa cell specific genes to establish these functionally distinct cell lineages. The mechanism establishing this precise morphogenic pattern of oocyte signaling within the follicle is unknown. The present study investigated a role for heparan sulphate proteoglycans (HSPG) as coreceptors mediating oocyte secreted factor signaling. In vitro maturation of cumulus oocyte complexes in the presence of exogenous heparin, which antagonizes HSPG signaling, prevented cumulus expansion and blocked the induction of cumulus-specific matrix genes, Has2 and Tnfaip6, whereas conversely, the mural granulosa-specific genes, Lhcgr and Cyp11a1, were strongly up-regulated. Heparin also blocked phosphorylation of SMAD2. Exogenous growth differentiation factor (GDF)-9 reversed these heparin effects; furthermore, GDF9 strongly bound to heparin sepharose. These observations indicate that heparin binds endogenous GDF9 and disrupts interaction with heparan sulphate proteoglycan coreceptor(s), important for GDF9 signaling. The expression of candidate HSPG coreceptors, Syndecan 1-4, Glypican 1-6, and Betaglycan, was examined. An ovulatory dose of human chorionic gonadotropin down-regulated Betaglycan in cumulus cells, and this regulation required GDF9 activity; conversely, Betaglycan was significantly increased in luteinizing mural granulosa cells. Human chorionic gonadotropin caused very strong induction of Syndecan 1 and Syndecan 4 in mural granulosa as well as cumulus cells. Glypican 1 was selectively induced in cumulus cells, and this expression appeared dependent on GDF9 action. These data suggest that HSPG play an essential role in GDF9 signaling and are involved in the patterning of oocyte signaling and cumulus cell function in the periovulatory follicle. (Endocrinology 153: 4544 -4555, 2012) O varian follicles coordinately respond to maternal endocrine and oocyte paracrine signals to mediate the maturation of oocytes and cyclic production of female reproductive hormones. The follicle comprises layers of somatic cells that proliferate and differentiate forming two phenotypically and functionally different cell populations: cumulus cells, which envelope the oocyte forming the cumulus oocyte complex (COC), and mural granulosa cells (GC), which line the follicle wall. These two cell types play distinct roles in the function of the follicle, together providing a specialized microenvironment in which the oocyte matures. Throughout folliculogenesis cumulus cells regulate the oocyte's microenvironment and energy supply via expression of genes required for carbohydrate metabolism and cholesterol biosynthesis. Mural granulosa cells participate in endocrine communication through expression of genes encoding steroidogenic enzymes and the LH receptor. Mural granulosa cells thus sense the LH surge and respond by activating ovulation and oocyte maturation cascades. Epidermal growth factor-like ligands released by granulosa cells trigger cumulus ce...

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Transient Invasive Migration in Mouse Cumulus Oocyte Complexes Induced at Ovulation by Luteinizing Hormone1

Cited by 43 publications

References 73 publications

Characterization of the human cumulus cell transcriptome during final follicular maturation and ovulation

Characterization of the human cumulus cell transcriptome during final follicular maturation and ovulation

A novel regulatory pathway in granulosa cells, the LH/human chorionic gonadotropin-microRNA-125a-3p-Fyn pathway, is required for ovulation

Heparan Sulfate Proteoglycans Regulate Responses to Oocyte Paracrine Signals in Ovarian Follicle Morphogenesis

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