Genes & Genomics

, Volume 40, Issue 3, pp 295–304 | Cite as

Characterization of the dynamic change of microRNA expression in mice hypothalamus during the time of female puberty

  • Gideon Omariba
  • Li Tong
  • Maochun Wang
  • Kai Li
  • Yuxun Zhou
  • Junhua Xiao
Research Article


Puberty onset is a milestone in sexual development. A tumor suppress gene (TSG) network had been reported to be involved in the regulation of female puberty onset. The observations in rodents and primates showed a potential link between microRNAs and puberty onset. To figure out what miRNAs play roles in this important biological process, profilings of microRNAs in the hypothalamus of female mice from three different pubertal stages, juvenile [postnatal day (P10)], early pubertal (P25) and pubertal (P30) were performed on the Affymetrix GeneChip miRNA 3.0 Arrays, the cerebral cortex (CTX) was used as a control tissue. 20 miRNAs were shown to be differentially expressed in hypothalamus (fold change > 1.5, P < 0.05), but not in CTX during the transition from juvenile to pubertal. Four of them were validated by real-time quantitative RT-PCR (qRT-PCR) method. 1018 genes were predicted as the targets of these miRNAs. Further bioinformatics analysis suggested that these target genes were involved in many important signaling pathways, especially in the cancer related pathways. We also found that about 90% of these target genes were expressed in the hypothalamus, as well as in the immortalized GnRH-producing GT1-7 cells, which provided additional evidence that these miRNAs could be female puberty onset related. Here we present a novel comprehensive data set of miRNA gene expression during the puberty onset; and it provides an important recourse for the future functional characterization of individual miRNAs and their targets in mouse hypothalamus and in GT1-7 cells.


Mouse hypothalamus MiRNA array Puberty onset Tumor related genes 



This work was supported by grants from the National Nature Science Foundation of China (Grant No. 31371257), and the Key Project of Science and Technology Commission of Shanghai Municipality (15140900500, 16140901302).

Compliance with ethical standards

Conflict of interest

Gideon Omariba declares that he does not have conflict of interest. Li Tong declares that she does not have conflict of interest. Maochun Wang declares that he does not have conflict of interest. Kai Li declares that he does not have conflict of interest. Yuxun Zhou declares that she does not have conflict of interest. Junhua Xiao declares that he does not have conflict of interest.

Ethical approval

All the experiments related to mice were approved by the Institutional Animal Care and Use Committee at Donghua University.

Supplementary material

13258_2017_633_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 18 KB)
13258_2017_633_MOESM2_ESM.xlsx (16 kb)
Supplementary material 2 (XLSX 16 KB)
13258_2017_633_MOESM3_ESM.pdf (359 kb)
Supplementary material 3 (PDF 358 KB)
13258_2017_633_MOESM4_ESM.pdf (173 kb)
Supplementary material 4 (PDF 173 KB)
13258_2017_633_MOESM5_ESM.pdf (147 kb)
Supplementary material 5 (PDF 147 KB)
13258_2017_633_MOESM6_ESM.tif (866 kb)
Supplementary material 6 (TIF 865 KB)


  1. Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P, Thompson IR, Navarro VM, Gagliardi PC (2013) Central precocious puberty caused by mutations in the imprinted gene MKRN3. New Engl J Med 368:2467–2475CrossRefPubMedGoogle Scholar
  2. Abreu AP, Macedo DB, Brito VN, Kaiser UB, Latronico AC (2015) A new pathway in the control of the initiation of puberty: the MKRN3 gene. J Mol Endocrinol 54:R131–R139CrossRefPubMedPubMedCentralGoogle Scholar
  3. Ahn HW, Morin RD, Zhao H, Harris RA, Coarfa C, Chen Z-J, Milosavljevic A, Marra MA, Rajkovic A (2010) MicroRNA transcriptome in the newborn mouse ovaries determined by massive parallel sequencing. Mol Human Reprod 16:463–471CrossRefGoogle Scholar
  4. Bak M, Silahtaroglu A, Møller M, Christensen M, Rath MF, Skryabin B, Tommerup N, Kauppinen S (2008) MicroRNA expression in the adult mouse central nervous system. RNA 14:432–444CrossRefPubMedPubMedCentralGoogle Scholar
  5. Cao X-n, Yan C, Liu D-y, Peng J-p, Chen J-j, Zhou Y, Long C-l, He D-w, Lin T, Shen L-j (2015) Fine particulate matter leads to reproductive impairment in male rats by overexpressing phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Toxicol Lett 237:181–190CrossRefPubMedGoogle Scholar
  6. Chekulaeva M, Filipowicz W (2009) Mechanisms of miRNA-mediated post-transcriptional regulation in animal cells. Curr Opin Cell Biol 21:452–460CrossRefPubMedGoogle Scholar
  7. Chen Y, Shin BC, Thamotharan S, Devaskar SU (2014) Differential methylation of the micro-RNA 7b gene targets postnatal maturation of murine neuronal Mecp2 gene expression. Dev Neurobiol 74:407–425CrossRefPubMedGoogle Scholar
  8. Dill H, Linder B, Fehr A, Fischer U (2012) Intronic miR-26b controls neuronal differentiation by repressing its host transcript, ctdsp2. Genes Dev 26:25–30CrossRefPubMedPubMedCentralGoogle Scholar
  9. Grieco A, Rzeczkowska P, Alm C, Palmert MR (2013) Investigation of peripubertal expression of Lin28a and Lin28b in C57BL/6 female mice. Mol Cell Endocrinol 365:241–248CrossRefPubMedGoogle Scholar
  10. Han W, Zou J, Wang K, Su Y, Zhu Y, Song C, Li G, Qu L, Zhang H, Liu H (2015) High-throughput sequencing reveals hypothalamic microRNAs as novel partners involved in timing the rapid development of chicken (Gallus gallus) gonads. PLoS ONE 10:e0129738CrossRefPubMedPubMedCentralGoogle Scholar
  11. He C, Kraft P, Chen C, Buring JE, Paré G, Hankinson SE, Chanock SJ, Ridker PM, Hunter DJ, Chasman DI (2009) Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat Genet 41:724–728CrossRefPubMedPubMedCentralGoogle Scholar
  12. Iughetti L, Casarosa E, Predieri B, Patianna V, Luisi S (2011) Plasma brain-derived neurotrophic factor concentrations in children and adolescents. Neuropeptides 45:205–211CrossRefPubMedGoogle Scholar
  13. Kochan DZ, Ilnytskyy Y, Golubov A, Deibel SH, McDonald RJ, Kovalchuk O (2015) Circadian disruption-induced microRNAome deregulation in rat mammary gland tissues. Oncoscience 2:428CrossRefPubMedPubMedCentralGoogle Scholar
  14. Lapointe E, Boerboom D (2011) Centre de recherche en reproduction animale, faculte de medecine veterinaire, Universite de Montreal, Saint-Hyacinthe, Quebec, Canada, J2S 7C6. Front Biosci 3:276–285Google Scholar
  15. Liposits Z, Merchenthaler I, Wetsel WC, Reid JJ, Mellon PL, Weiner RI, Negro-Vilar A (1991) Morphological characterization of immortalized hypothalamic neurons synthesizing luteinizing hormone-releasing hormone. Endocrinology 129:1575–1583CrossRefPubMedGoogle Scholar
  16. Lomniczi A, Wright H, Ojeda SR (2015) Epigenetic regulation of female puberty. Front Neuroendocrinol 36:90–107CrossRefPubMedGoogle Scholar
  17. Lynn FC (2009) Meta-regulation: microRNA regulation of glucose and lipid metabolism. Trends Endocrinol Metab 20:452–459CrossRefPubMedGoogle Scholar
  18. Meister B, Herzer S, Silahtaroglu A (2013) MicroRNAs in the hypothalamus. Neuroendocrinology 98:243–253CrossRefPubMedGoogle Scholar
  19. Millar RP, Lu Z-L, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR (2004) Gonadotropin-releasing hormone receptors. Endocr Rev 25:235–275CrossRefPubMedGoogle Scholar
  20. Morentin P, Martinez-Sanchez N, Roa J, Ferno J, Nogueiras R, Tena-Sempere M, Dieguez C, Lopez M (2014) Hypothalamic mTOR: the rookie energy sensor. Curr Mol Med 14:3–21CrossRefGoogle Scholar
  21. Novaira HJ, Ng Y, Wolfe A, Radovick S (2009) Kisspeptin increases GnRH mRNA expression and secretion in GnRH secreting neuronal cell lines. Mol Cell Endocrinol 311:126–134CrossRefPubMedPubMedCentralGoogle Scholar
  22. Ojeda SR, Skinner MK (2006) Puberty in the rat. In: Knobil and Neill’s physiology of reproduction. Elsevier Inc., AmsterdamGoogle Scholar
  23. Ojeda SR, Dubay C, Lomniczi A, Kaidar G, Matagne V, Sandau US, Dissen GA (2010a) Gene networks and the neuroendocrine regulation of puberty. Mol Cell Endocrinol 324:3–11CrossRefPubMedGoogle Scholar
  24. Ojeda SR, Lomniczi A, Sandau U, Matagne V (2010b) New concepts on the control of the onset of puberty. In: Pediatric neuroendocrinology, vol 17. Karger Publishers, Basel, pp 44–51CrossRefGoogle Scholar
  25. Olsen L, Klausen M, Helboe L, Nielsen FC, Werge T (2009) MicroRNAs show mutually exclusive expression patterns in the brain of adult male rats. PLoS ONE 4:e7225CrossRefPubMedPubMedCentralGoogle Scholar
  26. Parent A-S, Teilmann G, Juul A, Skakkebaek NE, Toppari J, Bourguignon J-P (2003) The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr Rev 24:668–693CrossRefPubMedGoogle Scholar
  27. Perry JR, Stolk L, Franceschini N, Lunetta KL, Zhai G, McArdle PF, Smith AV, Aspelund T, Bandinelli S, Boerwinkle E (2009) Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nat Genet 41:648–650CrossRefPubMedPubMedCentralGoogle Scholar
  28. Qiu X, Dao H, Wang M, Heston A, Garcia KM, Sangal A, Dowling AR, Faulkner LD, Molitor SC, Elias CF (2015) Insulin and leptin signaling interact in the mouse Kiss1 neuron during the peripubertal period. PLoS ONE 10:e0121974CrossRefPubMedPubMedCentralGoogle Scholar
  29. Rodgers AB, Morgan CP, Bronson SL, Revello S, Bale TL (2013) Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J Neurosci 33:9003–9012CrossRefPubMedPubMedCentralGoogle Scholar
  30. Roth CL, Mastronardi C, Lomniczi A, Wright H, Cabrera R, Mungenast AE, Heger S, Jung H, Dubay C, Ojeda SR (2007) Expression of a tumor-related gene network increases in the mammalian hypothalamus at the time of female puberty. Endocrinology 148:5147–5161CrossRefPubMedGoogle Scholar
  31. Salisbury TB, Binder AK, Nilson JH (2008) Welcoming β-catenin to the gonadotropin-releasing hormone transcriptional network in gonadotropes. Mol Endocrinol 22:1295–1303CrossRefPubMedPubMedCentralGoogle Scholar
  32. Sangiao-Alvarellos S, Manfredi-Lozano M, Ruiz-Pino F, Navarro V, Sanchez-Garrido M, León S, Diéguez C, Cordido F, Matagne V, Dissen G (2013) Changes in hypothalamic expression of the Lin28/let-7 system and related microRNAs during postnatal maturation and after experimental manipulations of puberty. Endocrinology 154:942–955CrossRefPubMedPubMedCentralGoogle Scholar
  33. Shenouda SK, Alahari SK (2009) MicroRNA function in cancer: oncogene or a tumor suppressor? Cancer Metastasis Rev 28:369–378CrossRefPubMedGoogle Scholar
  34. Sulem P, Gudbjartsson DF, Rafnar T, Holm H, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Alexandersen P, Feenstra B, Boyd HA (2009) Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche. Nat Genet 41:734–738CrossRefPubMedGoogle Scholar
  35. Viswanathan SR, Daley GQ (2010) Lin28: A microRNA regulator with a macro role. Cell 140:445–449CrossRefPubMedGoogle Scholar
  36. Xu G, Shi C, Ji C, Song G, Chen L, Yang L, Zhao Y, Guo X (2014) Expression of microRNA-26b, an obesity-related microRNA, is regulated by free fatty acids, glucose, dexamethasone and growth hormone in human adipocytes. Mol Med Rep 10:223–228CrossRefPubMedGoogle Scholar
  37. Xu G, Ji C, Song G, Zhao C, Shi C, Song L, Chen L, Yang L, Huang F, Pang L (2015) MiR-26b modulates insulin sensitivity in adipocytes by interrupting the PTEN/PI3K/AKT pathway. Int J Obes 39:1523–1530CrossRefGoogle Scholar

Copyright information

© The Genetics Society of Korea and Springer Science+Business Media B.V., part of Springer Nature 2017

Authors and Affiliations

  1. 1.The College of Chemistry, Chemical Engineering and BiotechnologyDonghua UniversityShanghaiChina

Personalised recommendations