Non-coding RNA in Ovarian Development and Disease

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 886)


The ovary’s primary function is to produce the mature female gamete, the oocyte that, following fertilization, can develop into an embryo, implant within the uterus and ultimately allow the mother’s genetic material to be passed along to subsequent generations. In addition to supporting the generation of the oocyte, the ovary and specific ephemeral tissues within it, follicles and corpora lutea, produce steroids that regulate all aspects of the reproductive system, including the hypothalamic/pituitary axis, the reproductive tract (uterus, oviduct, cervix), secondary sex characteristics all of which are also essential for pregnancy and subsequent nurturing of the offspring. To accomplish these critical roles, ovarian development and function are tightly regulated by a number of exogenous (hypothalamic/pituitary) and endogenous (intraovarian) hormones. Within ovarian cells, intricate signalling cascades and transcriptional and post-transcriptional gene regulatory networks respond to these hormonal influences to provide the exquisite control over all of the temporal and spatial events that must be synchronized to allow this organ to successfully complete its function. This book chapter will focus specifically on the role of non-coding RNAs, their identification and described functional roles within the ovary with respect to normal function and their possible involvement in diseases, which involve the ovary.


Folliculogenesis MicroRNA Premature ovarian failure Ovarian cancer Endo-siRNA Long non-coding RNA 


  1. Ahn HW et al (2010) MicroRNA transcriptome in the newborn mouse ovaries determined by massive parallel sequencing. Mol Hum Reprod 16(7):463–471CrossRefPubMedPubMedCentralGoogle Scholar
  2. Andl T et al (2006) The miRNA-processing enzyme dicer is essential for the morphogenesis and maintenance of hair follicles. Curr Biol 16(10):1041–1049CrossRefPubMedPubMedCentralGoogle Scholar
  3. Arango NA et al (2008) A mesenchymal perspective of müllerian duct differentiation and regression in Amhr2‐lacZ mice. Mol Reprod Dev 75(7):1154–1162CrossRefPubMedGoogle Scholar
  4. Ariel I et al (1995) The imprinted H19 gene as a tumor marker in bladder carcinoma. Urology 45(2):335–338CrossRefPubMedGoogle Scholar
  5. Bernstein E et al (2003) Dicer is essential for mouse development. Nat Genet 35(3):215–217CrossRefPubMedGoogle Scholar
  6. Blower PE et al (2008) MicroRNAs modulate the chemosensitivity of tumor cells. Mol Cancer Ther 7(1):1–9CrossRefPubMedGoogle Scholar
  7. Boren T et al (2009) MicroRNAs and their target messenger RNAs associated with ovarian cancer response to chemotherapy. Gynecol Oncol 113(2):249–255CrossRefPubMedGoogle Scholar
  8. Boutzios G, Karalaki M, Zapanti E (2013) Common pathophysiological mechanisms involved in luteal phase deficiency and polycystic ovary syndrome. Impact on fertility. Endocrine 43(2):314–317CrossRefPubMedGoogle Scholar
  9. Brewer CJ, Balen AH (2010) The adverse effects of obesity on conception and implantation. Reproduction 140(3):347–364CrossRefPubMedGoogle Scholar
  10. Buccione R, Schroeder AC, Eppig JJ (1990) Interactions between somatic cells and germ cells throughout mammalian oogenesis. Biol Reprod 43(4):543–547CrossRefPubMedGoogle Scholar
  11. Carletti M, Christenson LK (2009) MicroRNA in the ovary and female reproductive tract. J Anim Sci 87(14 suppl):E29–E38CrossRefPubMedGoogle Scholar
  12. Carletti MZ, Fiedler SD, Christenson LK (2010) MicroRNA 21 blocks apoptosis in mouse periovulatory granulosa cells. Biol Reprod 83(2):286CrossRefPubMedPubMedCentralGoogle Scholar
  13. Carrer M et al (2012) Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*. Proc Natl Acad Sci U S A 109(38):15330–15335CrossRefPubMedPubMedCentralGoogle Scholar
  14. Castillo AF et al (2011) Hormone-dependent expression of a steroidogenic acute regulatory protein natural antisense transcript in MA-10 mouse tumor Leydig cells. PLoS One 6(8):e22822CrossRefPubMedPubMedCentralGoogle Scholar
  15. Chen Y-H et al (2013) MiRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance. Diabetes 62:2278–2286CrossRefPubMedPubMedCentralGoogle Scholar
  16. Choi Y et al (2007) Microarray analyses of newborn mouse ovaries lacking Nobox. Biol Reprod 77(2):312–319CrossRefPubMedGoogle Scholar
  17. Cochrane DR et al (2010) Loss of miR-200c: a marker of aggressiveness and chemoresistance in female reproductive cancers. J Oncol 2009Google Scholar
  18. Cui X-S, Shen X-H, Kim N-H (2007) Dicer1 expression in preimplantation mouse embryos: involvement of Oct3/4 transcription at the blastocyst stage. Biochem Biophys Res Commun 352(1):231–236Google Scholar
  19. Di Leva G, Croce CM (2013) The role of microRNAs in the tumorigenesis of ovarian cancer. Front Oncol 3:153PubMedPubMedCentralGoogle Scholar
  20. Ehrmann DA (2005) Polycystic ovary syndrome. N Engl J Med 352(12):1223–1236CrossRefPubMedGoogle Scholar
  21. Eppig JJ (2001) Oocyte control of ovarian follicular development and function in mammals. Reproduction 122(6):829–838CrossRefPubMedGoogle Scholar
  22. Fiedler SD et al. (2008) MicroRNA expression within periovulatory mural granulosa cells. Biology Reproduction 79:1030–1037Google Scholar
  23. Franks S (1995) Polycystic ovary syndrome. N Engl J Med 333(13):853–861CrossRefPubMedGoogle Scholar
  24. Gifford JAH, Hunzicker-Dunn ME, Nilson JH (2009) Conditional deletion of beta-catenin mediated by Amhr2cre in mice causes female infertility. Biol Reprod 80(6):1282–1292CrossRefGoogle Scholar
  25. Gilchrist RB, Ritter LJ, Armstrong DT (2004) Oocyte–somatic cell interactions during follicle development in mammals. Anim Reprod Sci 82:431–446CrossRefPubMedGoogle Scholar
  26. Gonzalez G, Behringer RR (2009) Dicer is required for female reproductive tract development and fertility in the mouse. Mol Reprod Dev 76(7):678–688CrossRefPubMedPubMedCentralGoogle Scholar
  27. Harfe BD et al (2005) The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb. Proc Natl Acad Sci U S A 102(31):10898–10903CrossRefPubMedPubMedCentralGoogle Scholar
  28. Hong X et al (2008) Dicer1 is essential for female fertility and normal development of the female reproductive system. Endocrinology 149(12):6207–6212CrossRefPubMedPubMedCentralGoogle Scholar
  29. Hossain MM et al (2013) Altered expression of miRNAs in a dihydrotestosterone-induced rat PCOS model. J Ovarian Res 6(1):36CrossRefPubMedPubMedCentralGoogle Scholar
  30. Hussein-Fikret S, Fuller PJ (2005) Expression of nuclear receptor coregulators in ovarian stromal and epithelial tumours. Mol Cell Endocrinol 229(1–2):149–160CrossRefPubMedGoogle Scholar
  31. Knuutila S et al (1998) DNA copy number amplifications in human neoplasms: review of comparative genomic hybridization studies. Am J Pathol 152(5):1107PubMedPubMedCentralGoogle Scholar
  32. Kumar MS et al (2007) Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet 39(5):673–677CrossRefPubMedGoogle Scholar
  33. Kumarswamy R, Volkmann I, Thum T (2011) Regulation and function of miRNA-21 in health and disease. RNA Biol 8(5):706–713CrossRefPubMedPubMedCentralGoogle Scholar
  34. Kung JT, Colognori D, Lee JT (2013) Long noncoding RNAs: past, present, and future. Genetics 193(3):651–669CrossRefPubMedPubMedCentralGoogle Scholar
  35. Lau NC et al (2009) Abundant primary piRNAs, endo-siRNAs, and microRNAs in a Drosophila ovary cell line. Genome Res 19(10):1776–1785CrossRefPubMedPubMedCentralGoogle Scholar
  36. Lei L et al (2010) The regulatory role of Dicer in folliculogenesis in mice. Mol Cell Endocrinol 315(1):63–73CrossRefPubMedGoogle Scholar
  37. Li SD et al (2010) The role of microRNAs in ovarian cancer initiation and progression. J Cell Mol Med 14(9):2240–2249CrossRefPubMedPubMedCentralGoogle Scholar
  38. Li M et al (2011) Repertoire of porcine microRNAs in adult ovary and testis by deep sequencing. Int J Biol Sci 7(7):1045CrossRefPubMedPubMedCentralGoogle Scholar
  39. Liang Y et al (2007) Characterization of microRNA expression profiles in normal human tissues. BMC Genomics 8(1):166CrossRefPubMedPubMedCentralGoogle Scholar
  40. Liang M et al (2013) Transcriptional cooperation between p53 and NF-κB p65 regulates microRNA-224 transcription in mouse ovarian granulosa cells. Mol Cell Endocrinol 370:119–129CrossRefPubMedGoogle Scholar
  41. Lin F et al (2012) miR-26b promotes granulosa cell apoptosis by targeting ATM during follicular atresia in porcine ovary. PLoS ONE 7(6):e38640CrossRefPubMedPubMedCentralGoogle Scholar
  42. Luense LJ et al (2011) Developmental programming: gestational testosterone treatment alters fetal ovarian gene expression. Endocrinology 152(12):4974–4983CrossRefPubMedPubMedCentralGoogle Scholar
  43. Ma J et al (2010) MicroRNA activity is suppressed in mouse oocytes. Curr Biol 20(3):265–270CrossRefPubMedPubMedCentralGoogle Scholar
  44. Ma T et al (2011) Microarray analysis of differentially expressed microRNAs in non-regressed and regressed bovine corpus luteum tissue; microRNA-378 may suppress luteal cell apoptosis by targeting the interferon gamma receptor 1 gene. J Appl Genet 52(4):481–486CrossRefPubMedGoogle Scholar
  45. Mase Y et al (2012) MiR-21 is enriched in the RNA-induced silencing complex and targets COL4A1 in human granulosa cell lines. Reprod Sci 19:1030–1040CrossRefPubMedGoogle Scholar
  46. Mattiske DM, Han L, Mann JR (2009) Meiotic maturation failure induced by DICER1 deficiency is derived from primary oocyte ooplasm. Reproduction 137(4):625–632CrossRefPubMedGoogle Scholar
  47. McBride D et al (2012) Identification of miRNAs associated with the follicular-luteal transition in the ruminant ovary. Reproduction 144(2):221–233CrossRefPubMedGoogle Scholar
  48. Merritt WM et al (2008) Dicer, Drosha, and outcomes in patients with ovarian cancer. N Engl J Med 359(25):2641–2650CrossRefPubMedPubMedCentralGoogle Scholar
  49. Muljo SA et al (2005) Aberrant T cell differentiation in the absence of Dicer. J Exp Med 202(2):261–269CrossRefPubMedPubMedCentralGoogle Scholar
  50. Murchison EP et al (2007) Critical roles for Dicer in the female germline. Genes Dev 21(6):682–693CrossRefPubMedPubMedCentralGoogle Scholar
  51. Nagaraja AK et al (2008) Deletion of Dicer in somatic cells of the female reproductive tract causes sterility. Mol Endocrinol 22(10):2336–2352CrossRefPubMedPubMedCentralGoogle Scholar
  52. Otsuka M et al (2008) Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice. J Clin Invest 118(5):1944CrossRefPubMedPubMedCentralGoogle Scholar
  53. Pangas SA et al (2007) Intraovarian activins are required for female fertility. Mol Endocrinol 21(10):2458–2471CrossRefPubMedGoogle Scholar
  54. Pastorelli LM et al (2009) Genetic analyses reveal a requirement for Dicer1 in the mouse urogenital tract. Mamm Genome 20(3):140–151CrossRefPubMedGoogle Scholar
  55. Richards JS (1980) Maturation of ovarian follicles: actions and interactions of pituitary and ovarian hormones on follicular cell differentiation. Physiol Rev 60(1):51–89PubMedGoogle Scholar
  56. Richards JAS et al (2002a) Expression of FKHR, FKHRL1, and AFX genes in the rodent ovary: evidence for regulation by IGF-I, estrogen, and the gonadotropins. Mol Endocrinol 16(3):580CrossRefPubMedGoogle Scholar
  57. Richards JS et al (2002b) Novel signaling pathways that control ovarian follicular development, ovulation, and luteinization. Recent Prog Horm Res 57(1):195–220CrossRefPubMedGoogle Scholar
  58. Ro S et al (2007) Cloning and expression profiling of small RNAs expressed in the mouse ovary. RNA 13(12):2366–2380CrossRefPubMedPubMedCentralGoogle Scholar
  59. Sang Q et al (2013) Identification of microRNAs in human follicular fluid: characterization of microRNAs that govern steroidogenesis in vitro and are associated with polycystic ovary syndrome in vivo. J Clin Endocrinol Metab 98(7):3068–3079CrossRefPubMedGoogle Scholar
  60. Sirotkin AV et al (2009) Identification of MicroRNAs controlling human ovarian cell steroidogenesis via a genome‐scale screen. J Cell Physiol 219(2):415–420CrossRefPubMedGoogle Scholar
  61. Sorrentino A et al (2008) Role of microRNAs in drug-resistant ovarian cancer cells. Gynecol Oncol 111(3):478CrossRefPubMedGoogle Scholar
  62. Suh N et al (2010) MicroRNA function is globally suppressed in mouse oocytes and early embryos. Curr Biol 20(3):271–277CrossRefPubMedPubMedCentralGoogle Scholar
  63. Takada S et al (2006) Mouse microRNA profiles determined with a new and sensitive cloning method. Nucleic Acids Res 34(17):e115CrossRefPubMedPubMedCentralGoogle Scholar
  64. Tang F et al (2007) Maternal microRNAs are essential for mouse zygotic development. Genes Dev 21(6):644–648CrossRefPubMedPubMedCentralGoogle Scholar
  65. Tilly JL et al (1991) Involvement of apoptosis in ovarian follicular atresia and postovulatory regression. Endocrinology 129(5):2799–2801CrossRefPubMedGoogle Scholar
  66. Torley KJ et al (2011) Expression of miRNAs in ovine fetal gonads: potential role in gonadal differentiation. Reprod Biol Endocrinol 9:2CrossRefPubMedPubMedCentralGoogle Scholar
  67. Tripurani SK et al (2010) Cloning and analysis of fetal ovary microRNAs in cattle. Anim Reprod Sci 120(1):16–22CrossRefPubMedGoogle Scholar
  68. Veiga-Lopez A et al (2013) Developmental programming: gestational bisphenol-A treatment alters trajectory of fetal ovarian gene expression. Endocrinology 154(5):1873–1884CrossRefPubMedPubMedCentralGoogle Scholar
  69. Wang W et al (2011) Interference RNA-based silencing of endogenous SMAD4 in porcine granulosa cells resulted in decreased FSH-mediated granulosa cells proliferation and steroidogenesis. Reproduction 141(5):643–651CrossRefPubMedGoogle Scholar
  70. Watanabe T et al (2006) Identification and characterization of two novel classes of small RNAs in the mouse germline: retrotransposon-derived siRNAs in oocytes and germline small RNAs in testes. Genes Dev 20(13):1732–1743CrossRefPubMedPubMedCentralGoogle Scholar
  71. Watanabe T et al (2008) Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453(7194):539–543CrossRefPubMedGoogle Scholar
  72. Xu S et al (2011) Micro-RNA378 (miR-378) regulates ovarian estradiol production by targeting aromatase. Endocrinology 152(10):3941–3951CrossRefPubMedPubMedCentralGoogle Scholar
  73. Yan G et al (2012) MicroRNA-145 suppresses mouse granulosa cell proliferation by targeting activin receptor IB. FEBS Lett 586(19):3263–3270CrossRefPubMedGoogle Scholar
  74. Yang N et al (2008) MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer. Cancer Res 68(24):10307–10314CrossRefPubMedPubMedCentralGoogle Scholar
  75. Yang CX et al (2012a) Small RNA profile of the cumulus-oocyte complex and early embryos in the pig. Biol Reprod 87(5):117CrossRefPubMedGoogle Scholar
  76. Yang X et al (2012b) Differentially expressed plasma microRNAs in premature ovarian failure patients and the potential regulatory function of mir-23a in granulosa cell apoptosis. Reproduction 144(2):235–244CrossRefPubMedGoogle Scholar
  77. Yao N et al (2009) A network of miRNAs expressed in the ovary are regulated by FSH. Front Biosci 14:3239–3245CrossRefGoogle Scholar
  78. Yao G et al (2010a) MicroRNA-224 is involved in transforming growth factor-β-mediated mouse granulosa cell proliferation and granulosa cell function by targeting Smad4. Mol Endocrinol 24(3):540–551CrossRefPubMedPubMedCentralGoogle Scholar
  79. Yao N et al (2010b) Follicle-stimulating hormone regulation of microRNA expression on progesterone production in cultured rat granulosa cells. Endocrine 38(2):158–166CrossRefPubMedGoogle Scholar
  80. Yin M et al (2012a) Transactivation of microRNA-383 by steroidogenic factor-1 promotes estradiol release from mouse ovarian granulosa cells by targeting RBMS1. Mol Endocrinol 26(7):1129–1143CrossRefPubMedPubMedCentralGoogle Scholar
  81. Yin QF et al (2012b) Long noncoding RNAs with snoRNA ends. Mol Cell 48(2):219–230CrossRefPubMedGoogle Scholar
  82. Zhang L et al (2006) MicroRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci 103(24):9136–9141CrossRefPubMedPubMedCentralGoogle Scholar
  83. Zhang Q et al (2013) MicroRNA-181a suppresses mouse granulosa cell proliferation by targeting activin receptor IIA. PLoS ONE 8(3):e59667CrossRefPubMedPubMedCentralGoogle Scholar
  84. Zhao H, Rajkovic A (2008) MicroRNAs and mammalian ovarian development. In: Chegini N (ed) Seminars in reproductive medicine. © Thieme Medical Publishers, StuttgartGoogle Scholar
  85. Zhou Y, Zhu Y, Zhang SH, Wang HM, Wang SY, Yang XK (2011) MicroRNA expression profiles in premature ovarian failure patients and its potential regulate functions. Chin J Birth Health Hered 19:20–22Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  1. 1.Department of Molecular and Integrative PhysiologyUniversity of Kansas Medical CenterKansas CityUSA

Personalised recommendations