Regulation of ACVR1 and ID2 by cell-secreted exosomes during follicle maturation in the mare.
Abstract: Ovarian follicle growth and maturation requires extensive communication between follicular somatic cells and oocytes. Recently, intercellular cell communication was described involving cell-secreted vesicles called exosomes (50-150 nm), which contain miRNAs and protein, and have been identified in ovarian follicular fluid. The goal of this study was to identify a possible role of exosomes in follicle maturation. Methods: Follicle contents were collected from mares at mid-estrous (~35 mm, before induction of follicular maturation) and pre-ovulatory follicles (30-34 h after induction of follicular maturation). A real time PCR screen was conducted to reveal significant differences in the presence of exosomal miRNAs isolated from mid-estrous and pre-ovulatory follicles, and according to bioinformatics analysis these exosomal miRNAs are predicted to target members belonging to the TGFB superfamily, including ACVR1 and ID2. Granulosa cells from pre-ovulatory follicles were cultured and treated with exosomes isolated from follicular fluid. Changes in mRNA and protein were measured by real time PCR and Western blot. Results: ACVR1 mRNA and protein was detected in granulosa cells at mid-estrous and pre-ovulatory stages, and real time PCR analysis revealed significantly lower levels of ID2 (an ACVR1 target gene) in granulosa cells from pre-ovulatory follicles. Exposure to exosomes from follicular fluid of mid-estrous follicles decreased ID2 levels in granulosa cells. Moreover, exosomes isolated from mid-estrous and pre-ovulatory follicles contain ACVR1 and miR-27b, miR-372, and miR-382 (predicted regulators of ACVR1 and ID2) were capable of altering ID2 levels in pre-ovulatory granulosa cells. Conclusions: These data indicate that exosomes isolated from follicular fluid can regulate members of the TGFB/BMP signaling pathway in granulosa cells, and possibly play a role in regulating follicle maturation.
Publication Date: 2014-05-26 PubMed ID: 24884710PubMed Central: PMC4045866DOI: 10.1186/1477-7827-12-44Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
This research article reveals the regulatory role of cell-secreted exosomes in ovarian follicle maturation in mares. Specifically, the exosomes, which are small vesicles containing microRNAs and proteins, target the TGFB superfamily members ACVR1 and ID2, affecting changes in their mRNA and protein levels during follicular maturation stages.
Research Methods
- The primary methodological approach was the collection of follicle contents from mares at mid-estrous. This is a stage before the induction of follicular maturation, and pre-ovulatory follicles, which is 30-34 hours after the induction of follicular maturation.
- Through a real time PCR screen, the researchers were able to identify significant differences in exosomal microRNAs both at mid-estrous and pre-ovulatory stages.
- The study included a bioinformatics analysis which determined that these microRNAs target ACVR1 and ID2 of the TGFB superfamily.
- An additional part of the research involved culturing granulosa cells from pre-ovulatory follicles and then treating these cells with exosomes isolated from follicular fluid. The changes in mRNA and protein were noted via real time PCR and Western blot.
Research Findings
- In the granulosa cells at both mid-estrous and pre-ovulatory stages, ACVR1 mRNA and protein were detected.
- Through real time PCR analysis, the researchers discovered significantly lower levels of ID2 (a target gene of ACVR1) in granulosa cells from pre-ovulatory follicles.
- Exposure to exosomes from follicular fluid of mid-estrous follicles decreased ID2 levels in granulosa cells.
- The experiment verified that the exosomes, which contain ACVR1 and microRNA-27b, microRNA-372, and microRNA-382 (predicted regulators of ACVR1 and ID2), were capable of modifying ID2 levels in pre-ovulatory granulosa cells.
Conclusions
- Overall, the data from the research indicates that exosomes isolated from follicular fluid can regulate ACVR1 and ID2, members of the TGFB/BMP signaling pathway, in granulosa cells.
- This study suggests a potential role of exosomes in the intricate process of ovular follicle maturation. This could have profound implications on understanding the complexities of reproductive biology and potentially advancing reproductive technologies.
Cite This Article
APA
da Silveira JC, Carnevale EM, Winger QA, Bouma GJ.
(2014).
Regulation of ACVR1 and ID2 by cell-secreted exosomes during follicle maturation in the mare.
Reprod Biol Endocrinol, 12, 44.
https://doi.org/10.1186/1477-7827-12-44 Publication
Researcher Affiliations
- Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA. Gerrit.Bouma@colostate.edu.
MeSH Terms
- Activin Receptors, Type I / antagonists & inhibitors
- Activin Receptors, Type I / genetics
- Activin Receptors, Type I / metabolism
- Animals
- Cells, Cultured
- Colorado
- Computational Biology / methods
- Estrous Cycle / metabolism
- Exocytosis
- Exosomes / metabolism
- Female
- Follicular Fluid / cytology
- Follicular Fluid / metabolism
- Gene Expression Regulation, Developmental
- Granulosa Cells / cytology
- Granulosa Cells / metabolism
- Horses / physiology
- Inhibitor of Differentiation Protein 2 / antagonists & inhibitors
- Inhibitor of Differentiation Protein 2 / genetics
- Inhibitor of Differentiation Protein 2 / metabolism
- MicroRNAs / metabolism
- Oogenesis
- Ovarian Follicle / cytology
- Ovarian Follicle / metabolism
- RNA, Messenger / metabolism
- Signal Transduction
References
This article includes 34 references
- Fortune JE. Ovarian follicular growth and development in mammals.. Biol Reprod 1994 Feb;50(2):225-32.
- Knight PG, Glister C. TGF-beta superfamily members and ovarian follicle development.. Reproduction 2006 Aug;132(2):191-206.
- Matzuk MM, Burns KH, Viveiros MM, Eppig JJ. Intercellular communication in the mammalian ovary: oocytes carry the conversation.. Science 2002 Jun 21;296(5576):2178-80.
- Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends.. J Cell Biol 2013 Feb 18;200(4):373-83.
- da Silveira JC, Veeramachaneni DN, Winger QA, Carnevale EM, Bouma GJ. Cell-secreted vesicles in equine ovarian follicular fluid contain miRNAs and proteins: a possible new form of cell communication within the ovarian follicle.. Biol Reprod 2012 Mar;86(3):71.
- Sohel MM, Hoelker M, Noferesti SS, Salilew-Wondim D, Tholen E, Looft C, Rings F, Uddin MJ, Spencer TE, Schellander K, Tesfaye D. Exosomal and Non-Exosomal Transport of Extra-Cellular microRNAs in Follicular Fluid: Implications for Bovine Oocyte Developmental Competence.. PLoS One 2013;8(11):e78505.
- Bartel DP. MicroRNAs: target recognition and regulatory functions.. Cell 2009 Jan 23;136(2):215-33.
- Huntzinger E, Izaurralde E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay.. Nat Rev Genet 2011 Feb;12(2):99-110.
- Nagaraja AK, Andreu-Vieyra C, Franco HL, Ma L, Chen R, Han DY, Zhu H, Agno JE, Gunaratne PH, DeMayo FJ, Matzuk MM. Deletion of Dicer in somatic cells of the female reproductive tract causes sterility.. Mol Endocrinol 2008 Oct;22(10):2336-52.
- Carletti MZ, Christenson LK. MicroRNA in the ovary and female reproductive tract.. J Anim Sci 2009 Apr;87(14 Suppl):E29-38.
- Donadeu FX, Schauer SN, Sontakke SD. Involvement of miRNAs in ovarian follicular and luteal development.. J Endocrinol 2012 Dec;215(3):323-34.
- Yao G, Yin M, Lian J, Tian H, Liu L, Li X, Sun F. MicroRNA-224 is involved in transforming growth factor-beta-mediated mouse granulosa cell proliferation and granulosa cell function by targeting Smad4.. Mol Endocrinol 2010 Mar;24(3):540-51.
- Yin M, Lü M, Yao G, Tian H, Lian J, Liu L, Liang M, Wang Y, Sun F. Transactivation of microRNA-383 by steroidogenic factor-1 promotes estradiol release from mouse ovarian granulosa cells by targeting RBMS1.. Mol Endocrinol 2012 Jul;26(7):1129-43.
- Edson MA, Nagaraja AK, Matzuk MM. The mammalian ovary from genesis to revelation.. Endocr Rev 2009 Oct;30(6):624-712.
- Donadeu FX, Pedersen HG. Follicle development in mares.. Reprod Domest Anim 2008 Jul;43 Suppl 2:224-31.
- Carnevale EM, Maclellan LJ. Collection, evaluation, and use of oocytes in equine assisted reproduction.. Vet Clin North Am Equine Pract 2006 Dec;22(3):843-56.
- Bézard J, Mekarska A, Goudet G, Duchamp G, Palmer E. Timing of in vivo maturation of equine preovulatory oocytes and competence for in vitro maturation of immature oocytes collected simultaneously.. Equine Vet J Suppl 1997 Dec;(25):33-7.
- Théry C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids.. Curr Protoc Cell Biol 2006 Apr;Chapter 3:Unit 3.22.
- Davidson TR, Chamberlain CS, Bridges TS, Spicer LJ. Effect of follicle size on in vitro production of steroids and insulin-like growth factor (IGF)-I, IGF-II, and the IGF-binding proteins by equine ovarian granulosa cells.. Biol Reprod 2002 Jun;66(6):1640-8.
- Kayis SA, Atli MO, Kurar E, Bozkaya F, Semacan A, Aslan S, Guzeloglu A. Rating of putative housekeeping genes for quantitative gene expression analysis in cyclic and early pregnant equine endometrium.. Anim Reprod Sci 2011 May;125(1-4):124-32.
- Klein C, Rutllant J, Troedsson MH. Expression stability of putative reference genes in equine endometrial, testicular, and conceptus tissues.. BMC Res Notes 2011 Apr 12;4:120.
- Vlachos IS, Kostoulas N, Vergoulis T, Georgakilas G, Reczko M, Maragkakis M, Paraskevopoulou MD, Prionidis K, Dalamagas T, Hatzigeorgiou AG. DIANA miRPath v.2.0: investigating the combinatorial effect of microRNAs in pathways.. Nucleic Acids Res 2012 Jul;40(Web Server issue):W498-504.
- Shimizu T, Jayawardana BC, Nishimoto H, Kaneko E, Tetsuka M, Miyamoto A. Involvement of the bone morphogenetic protein/receptor system during follicle development in the bovine ovary: Hormonal regulation of the expression of bone morphogenetic protein 7 (BMP-7) and its receptors (ActRII and ALK-2).. Mol Cell Endocrinol 2006 Apr 25;249(1-2):78-83.
- Glister C, Satchell L, Knight PG. Changes in expression of bone morphogenetic proteins (BMPs), their receptors and inhibin co-receptor betaglycan during bovine antral follicle development: inhibin can antagonize the suppressive effect of BMPs on thecal androgen production.. Reproduction 2010 Nov;140(5):699-712.
- Johnson AL, Haugen MJ, Woods DC. Role for inhibitor of differentiation/deoxyribonucleic acid-binding (Id) proteins in granulosa cell differentiation.. Endocrinology 2008 Jun;149(6):3187-95.
- Verbraak EJ, van 't Veld EM, Groot Koerkamp M, Roelen BA, van Haeften T, Stoorvogel W, Zijlstra C. Identification of genes targeted by FSH and oocytes in porcine granulosa cells.. Theriogenology 2011 Jan 15;75(2):362-76.
- Karaya K, Mori S, Kimoto H, Shima Y, Tsuji Y, Kurooka H, Akira S, Yokota Y. Regulation of Id2 expression by CCAAT/enhancer binding protein beta.. Nucleic Acids Res 2005;33(6):1924-34.
- Sterneck E, Tessarollo L, Johnson PF. An essential role for C/EBPbeta in female reproduction.. Genes Dev 1997 Sep 1;11(17):2153-62.
- Song H, Wang Q, Wen J, Liu S, Gao X, Cheng J, Zhang D. ACVR1, a therapeutic target of fibrodysplasia ossificans progressiva, is negatively regulated by miR-148a.. Int J Mol Sci 2012;13(2):2063-2077.
- McBride D, Carré W, Sontakke SD, Hogg CO, Law A, Donadeu FX, Clinton M. Identification of miRNAs associated with the follicular-luteal transition in the ruminant ovary.. Reproduction 2012 Aug;144(2):221-33.
- Sirotkin AV, Lauková M, Ovcharenko D, Brenaut P, Mlyncek M. Identification of microRNAs controlling human ovarian cell proliferation and apoptosis.. J Cell Physiol 2010 Apr;223(1):49-56.
- Hossain MM, Ghanem N, Hoelker M, Rings F, Phatsara C, Tholen E, Schellander K, Tesfaye D. Identification and characterization of miRNAs expressed in the bovine ovary.. BMC Genomics 2009 Sep 18;10:443.
- Hong BS, Cho JH, Kim H, Choi EJ, Rho S, Kim J, Kim JH, Choi DS, Kim YK, Hwang D, Gho YS. Colorectal cancer cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cells.. BMC Genomics 2009 Nov 25;10:556.
- Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.. Nat Cell Biol 2007 Jun;9(6):654-9.
Citations
This article has been cited 28 times.- Surugaya R, Hasegawa Y, Adachi S, Ijiri S. Changes in Ovulation-Related Gene Expression during Induced Ovulation in the Amur Sturgeon (Acipenser schrenckii) Ovarian Follicles.. Int J Mol Sci 2022 Oct 29;23(21).
- Jankovičová J, Sečová P, Horovská Ľ, Olexiková L, Dujíčková L, Makarevich AV, Michalková K, Antalíková J. Distribution of tetraspanins in bovine ovarian tissue and fresh/vitrified oocytes.. Histochem Cell Biol 2023 Feb;159(2):163-183.
- Shen Y, You Y, Zhu K, Fang C, Chang D, Yu X. Exosomes in the f ield of reproduction: A scientometric study and visualization analysis.. Front Pharmacol 2022;13:1001652.
- Godakumara K, Dissanayake K, Hasan MM, Kodithuwakku SP, Fazeli A. Role of extracellular vesicles in intercellular communication during reproduction.. Reprod Domest Anim 2022 Oct;57 Suppl 5(Suppl 5):14-21.
- Widmer S, Seefried FR, von Rohr P, Häfliger IM, Spengeler M, Drögemüller C. Associated regions for multiple birth in Brown Swiss and Original Braunvieh cattle on chromosomes 15 and 11.. Anim Genet 2022 Oct;53(5):557-569.
- Gurunathan S, Kang MH, Song H, Kim NH, Kim JH. The role of extracellular vesicles in animal reproduction and diseases.. J Anim Sci Biotechnol 2022 Jun 10;13(1):62.
- Sysoeva AP, Makarova NP, Silachev DN, Lobanova NN, Shevtsova YA, Bragina EE, Kalinina EA, Sukhikh GT. Influence of Extracellular Vesicles of the Follicular Fluid on Morphofunctional Characteristics of Human Sperm.. Bull Exp Biol Med 2021 Dec;172(2):254-262.
- Adolfi MC, Du K, Kneitz S, Cabau C, Zahm M, Klopp C, Feron R, Paixão RV, Varela ES, de Almeida FL, de Oliveira MA, Nóbrega RH, Lopez-Roques C, Iampietro C, Lluch J, Kloas W, Wuertz S, Schaefer F, Stöck M, Guiguen Y, Schartl M. A duplicated copy of id2b is an unusual sex-determining candidate gene on the Y chromosome of arapaima (Arapaima gigas).. Sci Rep 2021 Nov 3;11(1):21544.
- Gebremedhn S, Ali A, Gad A, Prochazka R, Tesfaye D. Extracellular Vesicles as Mediators of Environmental and Metabolic Stress Coping Mechanisms During Mammalian Follicular Development.. Front Vet Sci 2020;7:602043.
- de Ávila ACFCM, Andrade GM, Bridi A, Gimenes LU, Meirelles FV, Perecin F, da Silveira JC. Extracellular vesicles and its advances in female reproduction.. Anim Reprod 2020 May 22;16(1):31-38.
- Pritchard N, Kaitu'u-Lino T, Harris L, Tong S, Hannan N. Nanoparticles in pregnancy: the next frontier in reproductive therapeutics.. Hum Reprod Update 2021 Feb 19;27(2):280-304.
- Qamar AY, Mahiddine FY, Bang S, Fang X, Shin ST, Kim MJ, Cho J. Extracellular Vesicle Mediated Crosstalk Between the Gametes, Conceptus, and Female Reproductive Tract.. Front Vet Sci 2020;7:589117.
- Lee SH, Saadeldin IM. Exosomes as a Potential Tool for Supporting Canine Oocyte Development.. Animals (Basel) 2020 Oct 27;10(11).
- Jankovičová J, Sečová P, Michalková K, Antalíková J. Tetraspanins, More than Markers of Extracellular Vesicles in Reproduction.. Int J Mol Sci 2020 Oct 14;21(20).
- Matsuno Y, Maruyama N, Fujii W, Naito K, Sugiura K. Effects of oocyte-derived paracrine factors on release of extracellular vesicles by murine mural granulosa cells in vitro.. Anim Sci J 2020 Jan-Dec;91(1):e13385.
- Salilew-Wondim D, Gebremedhn S, Hoelker M, Tholen E, Hailay T, Tesfaye D. The Role of MicroRNAs in Mammalian Fertility: From Gametogenesis to Embryo Implantation.. Int J Mol Sci 2020 Jan 16;21(2).
- Valer JA, Sánchez-de-Diego C, Pimenta-Lopes C, Rosa JL, Ventura F. ACVR1 Function in Health and Disease.. Cells 2019 Oct 31;8(11).
- Matsuno Y, Kanke T, Maruyama N, Fujii W, Naito K, Sugiura K. Characterization of mRNA profiles of the exosome-like vesicles in porcine follicular fluid.. PLoS One 2019;14(6):e0217760.
- Carossino M, Dini P, Kalbfleisch TS, Loynachan AT, Canisso IF, Shuck KM, Timoney PJ, Cook RF, Balasuriya UBR. Downregulation of MicroRNA eca-mir-128 in Seminal Exosomes and Enhanced Expression of CXCL16 in the Stallion Reproductive Tract Are Associated with Long-Term Persistence of Equine Arteritis Virus.. J Virol 2018 May 1;92(9).
- Hung WT, Navakanitworakul R, Khan T, Zhang P, Davis JS, McGinnis LK, Christenson LK. Stage-specific follicular extracellular vesicle uptake and regulation of bovine granulosa cell proliferation.. Biol Reprod 2017 Oct 1;97(4):644-655.
- Clarke HJ. Regulation of germ cell development by intercellular signaling in the mammalian ovarian follicle.. Wiley Interdiscip Rev Dev Biol 2018 Jan;7(1).
- Liu A, Wang Y, Sahana G, Zhang Q, Liu L, Lund MS, Su G. Genome-wide Association Studies for Female Fertility Traits in Chinese and Nordic Holsteins.. Sci Rep 2017 Aug 16;7(1):8487.
- da Silveira JC, Andrade GM, Del Collado M, Sampaio RV, Sangalli JR, Silva LA, Pinaffi FVL, Jardim IB, Cesar MC, Nogueira MFG, Cesar ASM, Coutinho LL, Pereira RW, Perecin F, Meirelles FV. Supplementation with small-extracellular vesicles from ovarian follicular fluid during in vitro production modulates bovine embryo development.. PLoS One 2017;12(6):e0179451.
- Matsuno Y, Onuma A, Fujioka YA, Yasuhara K, Fujii W, Naito K, Sugiura K. Effects of exosome-like vesicles on cumulus expansion in pigs in vitro.. J Reprod Dev 2017 Feb 16;63(1):51-58.
- Navakanitworakul R, Hung WT, Gunewardena S, Davis JS, Chotigeat W, Christenson LK. Characterization and Small RNA Content of Extracellular Vesicles in Follicular Fluid of Developing Bovine Antral Follicles.. Sci Rep 2016 May 9;6:25486.
- Di Pietro C. Exosome-mediated communication in the ovarian follicle.. J Assist Reprod Genet 2016 Mar;33(3):303-311.
- Machtinger R, Laurent LC, Baccarelli AA. Extracellular vesicles: roles in gamete maturation, fertilization and embryo implantation.. Hum Reprod Update 2016 Mar-Apr;22(2):182-93.
- Hung WT, Hong X, Christenson LK, McGinnis LK. Extracellular Vesicles from Bovine Follicular Fluid Support Cumulus Expansion.. Biol Reprod 2015 Nov;93(5):117.
Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists