Skip to main content
SpringerLink
Log in

Role of RFRP-3 in the Regulation of Kiss-1 Gene Expression in the AVPV Hypothalamic Cell Model mHypoA-50

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Kisspeptin, encoded by the Kiss-1 gene, plays a crucial role in reproductive function by governing the hypothalamic—pituitary—gonadal axis. The recently established Kiss-1-expressing cell model mHypoA-50 displays characteristics of neuronal cells of the anteroventral periventricular (AVPV) region of the mouse hypothalamus. Because Kiss-1 gene expression in these cells is upregulated by estradiol (E2), mHypoA-50 cells are regarded as a valuable model for the study of Kiss-1-expressing neurons in the AVPV region. These cells also express RFamide-related peptide-3 (RFRP-3), a mammalian homolog of gonadotropin inhibitory hormone. The RFRP-3 expression in mHypoA-50 cells was increased by melatonin stimulation. In addition, E2 stimulation increased RFRP-3 expression in these cells. Treatment of the mHypoA-50 cells with exogenous RFRP-3 resulted in the increase of Kiss-1 messenger RNA expression within the cells; however, RFRP-3 did not modify gonadotropin-releasing hormone or kisspeptin-induced Kiss-1 gene expression in these cells. In addition, we found that RFRP-3 stimulation increased the expression of corticotropin-releasing hormone, which may be involved in E2-induced positive feedback in mHypoA-50 cells. Our observations suggest that RFRP-3 might be involved in positive feedback regulation by directly or indirectly increasing Kiss-1 gene expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A. 2003;100(19):10972–10976.

    PubMed  PubMed Central  Google Scholar 

  2. Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349(17):1614–1627.

    CAS  PubMed  Google Scholar 

  3. Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology. 2005;146(9):3686–3692.

    CAS  PubMed  Google Scholar 

  4. Adachi S, Yamada S, Takatsu Y, et al. Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats. J Reprod Dev. 2007;53(2):367–378.

    CAS  PubMed  Google Scholar 

  5. Kinoshita M, Tsukamura H, Adachi S, et al. Involvement of central metastin in the regulation of preovulatory luteinizing hormone surge and estrous cyclicity in female rats. Endocrinology. 2005;146(10):4431–4436.

    CAS  PubMed  Google Scholar 

  6. Treen AK, Luo V, Chalmers JA, et al. Divergent regulation of ER and Kiss genes by 17beta-estradiol in hypothalamic ARC versus AVPV models. Mol Endocrinol. 2016;30(2):217–233.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Hinuma S, Shintani Y, Fukusumi S, et al. New neuropeptides containing carboxy-terminal RFamide and their receptor in mammals. Nat Cell Biol. 2000;2(10):703–708.

    CAS  PubMed  Google Scholar 

  8. Tsutsui K, Saigoh E, Ukena K, et al. A novel avian hypothalamic peptide inhibiting gonadotropin release. Biochem Biophys Res Commun. 2000;275(2):661–667.

    CAS  PubMed  Google Scholar 

  9. Ubuka T, Son YL, Tsutsui K. Molecular, cellular, morphological, physiological and behavioral aspects of gonadotropin-inhibitory hormone. Gen Comp Endocrinol. 2016;227:27–50.

    CAS  PubMed  Google Scholar 

  10. Anderson GM, Relf HL, Rizwan MZ, Evans JJ. Central and peripheral effects of RFamide-related peptide-3 on luteinizing hormone and prolactin secretion in rats. Endocrinology. 2009;150(4):1834–1840.

    CAS  PubMed  Google Scholar 

  11. Ancel C, Bentsen AH, Sébert ME, Tena-Sempere M, Mikkelsen JD, Simonneaux V. Stimulatory effect of RFRP-3 on the gonadotrophic axis in the male Syrian hamster: the exception proves the rule. Endocrinology. 2012;153(3):1352–1363.

    CAS  PubMed  Google Scholar 

  12. Ubuka T, Inoue K, Fukuda Y, et al. Identification, expression, and physiological functions of Siberian hamster gonadotropin-inhibitory hormone. Endocrinology. 2012;153(1):373–385.

    CAS  PubMed  Google Scholar 

  13. Henningsen JB, Ancel C, Mikkelsen JD, Gauer F, Simonneaux V, et al. Roles of RFRP-3 in the daily and seasonal regulation of reproductive activity in female Syrian hamsters. Endocrinology. 2017;158(3):652–663.

    CAS  PubMed  Google Scholar 

  14. Yano T, Iijima N, Kakihara K, Hinuma S, Tanaka M, Ibata Y. Localization and neuronal response of RFamide related peptides in the rat central nervous system. Brain Res. 2003;982(2):156–167.

    CAS  PubMed  Google Scholar 

  15. Poling MC, Quennell JH, Anderson GM, Kauffman AS. Kisspeptin neurones do not directly signal to RFRP-3 neurones but RFRP-3 may directly modulate a subset of hypothalamic kisspeptin cells in mice. J Neuroendocrinol. 2013;25(10):876–886.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Wong ML, Medrano JF. Real-time PCR for mRNA quantitation. Biotechniques. 2005;39(1):75–85.

    CAS  PubMed  Google Scholar 

  17. Bustin SA, Benes V, Nolan T, Pfaffl MW. Quantitative real-time RT-PCR—a perspective. J Mol Endocrinol. 2005;34(3):597–601.

    CAS  PubMed  Google Scholar 

  18. Underwood H, Binkley S, Siopes T, Mosher K. Melatonin rhythms in the eyes, pineal bodies, and blood of Japanese quail (Coturnix coturnix japonica). Gen Comp Endocrinol. 1984;56(1):70–81.

    CAS  PubMed  Google Scholar 

  19. Ubuka T, Bentley GE, Ukena K, Wingfield JC, Tsutsui K. Melatonin induces the expression of gonadotropin-inhibitory hormone in the avian brain. Proc Natl Acad Sci U S A. 2005;102(8):3052–3057.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sukhbaatar U, Kanasaki H, Mijiddorj T, et al. Expression of GnRH and kisspeptin in primary cultures of fetal rat brain. Reprod Sci. 2017;24(2):227–233.

    CAS  PubMed  Google Scholar 

  21. Tumurbaatar T, Kanasaki H, Oride A, et al. Action of neurotensin, CRH, and RFRP-3 in E2-induced negative feedback control: studies using a mouse ARC hypothalamic cell model. Biol Reprod. 2018.

  22. Smith JT, Popa SM, Clifton DK, Hoffman GE, Steiner RA. Kiss1 neurons in the forebrain as central processors for generating the preovulatory luteinizing hormone surge. J Neurosci. 2006;26(25):6687–6694.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Desroziers E, Mikkelsen J, Simonneaux V, et al. Mapping of kisspeptin fibres in the brain of the pro-oestrous rat. J Neuroendocrinol. 2010;22(10):1101–1112.

    CAS  PubMed  Google Scholar 

  24. Kriegsfeld LJ, Mei DF, Bentley GE, et al. Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals. Proc Natl Acad Sci U S A. 2006;103(7):2410–2415.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Mason AO, Duffy S, Zhao S, et al. Photoperiod and reproductive condition are associated with changes in RFamide-related peptide (RFRP) expression in Syrian hamsters (Mesocricetus auratus). J Biol Rhythms. 2010;25(3):176–185.

    PubMed  PubMed Central  Google Scholar 

  26. Chowdhury VS, Yamamoto K, Ubuka T, Bentley GE, Hattori A, Tsutsui K. Melatonin stimulates the release of gonadotropin-inhibitory hormone by the avian hypothalamus. Endocrinology. 2010;151(1):271–280.

    CAS  PubMed  Google Scholar 

  27. Revel FG, Saboureau M, Pévet P, Simonneaux V, Mikkelsen JD. RFamide-related peptide gene is a melatonin-driven photoperiodic gene. Endocrinology. 2008;149(3):902–912.

    CAS  PubMed  Google Scholar 

  28. Smith JT, Coolen LM, Kriegsfeld LJ, et al. Variation in kisspeptin and RFamide-related peptide (RFRP) expression and terminal connections to gonadotropin-releasing hormone neurons in the brain: a novel medium for seasonal breeding in the sheep. Endocrinology. 2008;149(11):5770–5782.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Gibson EM, Humber SA, Jain S, et al. Alterations in RFamide-related peptide expression are coordinated with the preovulatory luteinizing hormone surge. Endocrinology. 2008;149(10):4958–4969.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Clarke IJ, Smith JT, Henry BA, et al. Gonadotropin-inhibitory hormone is a hypothalamic peptide that provides a molecular switch between reproduction and feeding. Neuroendocrinology. 2012;95(4):305–316.

    CAS  PubMed  Google Scholar 

  31. Peng J, Long B, Yuan J, et al. A quantitative analysis of the distribution of CRH neurons in whole mouse brain. Front Neuroanat. 2017;11:63.

    PubMed  PubMed Central  Google Scholar 

  32. Kerdelhue B, Jones GS, Gordon K, et al. Activation of the hypothalamo-anterior pituitary corticotropin-releasing hormone, adrenocorticotropin hormone and beta-endorphin systems during the estradiol 17 beta-induced plasma LH surge in the ovariectomized monkey. J Neurosci Res. 1995;42(2):228–235.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, School of Medicine, Shimane University, 89-1 Enya Cho, Izumo, Shimane, 8501, Japan

    Haruhiko Kanasaki MD, PhD, Tuvshintugs Tumurbaatar MD, Aki Oride MD, PhD, Zolzaya Tumurgan MD, Hiroe Okada MD, Tomomi Hara MD & Satoru Kyo MD, PhD

  2. Laboratory of Integrative Brain Science, Department of Biology, Waseda University and Center for Medical Life Science of Waseda University, Tokyo, Japan

    Kazuyoshi Tsutsui PhD

Authors
  1. Haruhiko Kanasaki MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tuvshintugs Tumurbaatar MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aki Oride MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zolzaya Tumurgan MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroe Okada MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tomomi Hara MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazuyoshi Tsutsui PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Satoru Kyo MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haruhiko Kanasaki MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kanasaki, H., Tumurbaatar, T., Oride, A. et al. Role of RFRP-3 in the Regulation of Kiss-1 Gene Expression in the AVPV Hypothalamic Cell Model mHypoA-50. Reprod. Sci. 26, 1249–1255 (2019). https://doi.org/10.1177/1933719118813456

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719118813456

Keywords

Search

Navigation