Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Female reproductive maturation in the absence of kisspeptin/GPR54 signaling

Abstract

Puberty onset is initiated in the brain by activation of gonadotropin-releasing hormone (GnRH) neurosecretion. Different permissive signals must be integrated for the initiation of reproductive maturation; however, the neural circuits controlling timely awakening of the reproductive axis are not understood. The identification of the neuropeptide kisspeptin as a potent activator of GnRH neuronal activity suggests that kisspeptin-releasing neurons might coordinate puberty onset. To test this hypothesis, we generated mice that specifically lack kisspeptin cells. Puberty onset in females was unaffected by kisspeptin neuron ablation. Furthermore, the animals were fertile, albeit with smaller ovaries. Consistent with this, female mice lacking neurons that express the kisspeptin receptor GPR54 were also fertile. Acute ablation of kisspeptin neurons in adult mice inhibited fertility, suggesting that there is compensation for the loss of kisspeptin neurons early in development. Our data indicate that the initiation and completion of reproductive maturation can occur in the absence of kisspeptin/GPR54 signaling.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Targeted ablation of kisspeptin neurons.
Figure 2: Sexual maturation in female mice lacking kisspeptin neurons.
Figure 3: Genetic ablation of GPR54 neurons.
Figure 4: Unaltered timing of puberty onset in female mice lacking GPR54 neurons.
Figure 5: Acyclicity after diphtheria toxin–mediated ablation of kisspeptin neurons in adult KissIC/R26-iDTR mice.

Similar content being viewed by others

References

  1. Sisk, C.L. & Foster, D.L. The neural basis of puberty and adolescence. Nat. Neurosci. 7, 1040–1047 (2004).

    Article  CAS  Google Scholar 

  2. Terasawa, E. & Fernandez, D. Neurobiological mechanisms of the onset of puberty in primates. Endocr. Rev. 22, 111–151 (2001).

    CAS  PubMed  Google Scholar 

  3. Harris, G.C. & Levine, J.E. Pubertal acceleration of pulsatile gonadotropin-releasing hormone release in male rats as revealed by microdialysis. Endocrinology 144, 163–171 (2003).

    Article  CAS  Google Scholar 

  4. Ojeda, S.R. & Skinner, M.K. Puberty in the rat. in Knobil and Neill's Physiology of Reproduction (ed. Neill, J.D.) 2061–2126 (Elsevier Academic Press, St. Louis, 2006).

  5. Seminara, S.B. & Crowley, W. Kisspeptin and GPR54: discovery of a novel pathway in reproduction. J. Neuroendocrinol. 20, 727–731 (2008).

    Article  CAS  Google Scholar 

  6. Clarkson, J., Han, S.K., Liu, X., Lee, K. & Herbison, A.E. Neurobiological mechanisms underlying kisspeptin activation of gonadotropin-releasing hormone (GnRH) neurons at puberty. Mol. Cell Endocrinol. 324, 45–50 (2010).

    Article  CAS  Google Scholar 

  7. Kauffman, A.S., Clifton, D.K. & Steiner, R.A. Emerging ideas about kisspeptin-GPR54 signaling in the neuroendocrine regulation of reproduction. Trends Neurosci. 30, 504–511 (2007).

    Article  CAS  Google Scholar 

  8. Tena-Sempere, M. Roles of kisspeptins in the control of hypothalamic-gonadotropic function: focus on sexual differentiation and puberty onset. Endocr. Dev. 17, 52–62 (2010).

    Article  CAS  Google Scholar 

  9. de Roux, N. et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc. Natl. Acad. Sci. USA 100, 10972–10976 (2003).

    Article  CAS  Google Scholar 

  10. Seminara, S.B. et al. The GPR54 gene as a regulator of puberty. N. Engl. J. Med. 349, 1614–1627 (2003).

    Article  CAS  Google Scholar 

  11. d'Anglemont de Tassigny, X. et al. Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc. Natl. Acad. Sci. USA 104, 10714–10719 (2007).

    Article  CAS  Google Scholar 

  12. Lapatto, R. et al. Kiss1−/− mice exhibit more variable hypogonadism than Gpr54−/− mice. Endocrinology 148, 4927–4936 (2007).

    Article  CAS  Google Scholar 

  13. Funes, S. et al. The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem. Biophys. Res. Commun. 312, 1357–1363 (2003).

    Article  CAS  Google Scholar 

  14. Irwig, M.S et al. Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 80, 264–272 (2004).

    Article  CAS  Google Scholar 

  15. Messager, S. et al. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein–coupled receptor 54. Proc. Natl. Acad. Sci. USA 102, 1761–1766 (2005).

    Article  CAS  Google Scholar 

  16. Matsui, H., Takatsu, Y., Kumano, S., Matsumoto, H. & Ohtaki, T. Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem. Biophys. Res. Commun. 320, 383–388 (2004).

    Article  CAS  Google Scholar 

  17. Navarro, V.M. et al. Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54. J. Physiol. (Lond.) 561, 379–386 (2004).

    Article  CAS  Google Scholar 

  18. Pineda, R. et al. Critical roles of kisspeptins in female puberty and preovulatory gonadotropin surges as revealed by a novel antagonist. Endocrinology 151, 722–730 (2010).

    Article  CAS  Google Scholar 

  19. Mayer, C. et al. Timing and completion of puberty in female mice depend on estrogen receptor α signaling in kisspeptin neurons. Proc. Natl. Acad. Sci. USA 107, 22693–22698 (2010).

    Article  CAS  Google Scholar 

  20. Brockschnieder, D., Pechmann, Y., Sonnenberg-Riethmacher, E. & Riethmacher, D. An improved mouse line for Cre-induced cell ablation due to diphtheria toxin A, expressed from the Rosa26 locus. Genesis 44, 322–327 (2006).

    Article  CAS  Google Scholar 

  21. Collier, R.J. Understanding the mode of action of diphtheria toxin: a perspective on progress during the 20th century. Toxicon 39, 1793–1803 (2001).

    Article  CAS  Google Scholar 

  22. Franceschini, I. et al. Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus coexpress estrogen receptor alpha. Neurosci. Lett. 401, 225–230 (2006).

    Article  CAS  Google Scholar 

  23. Clarkson, J. & Herbison, A. Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology 147, 5817–5825 (2006).

    Article  CAS  Google Scholar 

  24. Clarkson, J., d'Anglemont de Tassigny, X., Colledge, W.H., Caraty, A. & Herbison, A.E. Distribution of kisspeptin neurones in the adult female mouse brain. J. Neuroendocrinol. 21, 673–682 (2009).

    Article  CAS  Google Scholar 

  25. Oakley, A.E., Clifton, D. & Steiner, R. Kisspeptin signaling in the brain. Endocr. Rev. 30, 713–743 (2009).

    Article  CAS  Google Scholar 

  26. Wen, S. et al. Genetic identification of GnRH receptor neurons: a new model for studying neural circuits underlying reproductive physiology in the mouse brain. Endocrinology 152, 1515–1526 (2011).

    Article  CAS  Google Scholar 

  27. Herbison, A.E., de Tassigny, X., Doran, J. & Colledge, W.H. Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin-releasing hormone neurons. Endocrinology 151, 312–321 (2010).

    Article  CAS  Google Scholar 

  28. Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001).

    Article  CAS  Google Scholar 

  29. Buch, T. et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat. Methods 2, 419–426 (2005).

    Article  CAS  Google Scholar 

  30. Castellano, J.M. et al. Expression of KiSS-1 in rat ovary: putative local regulator of ovulation? Endocrinology 147, 4852–4862 (2006).

    Article  CAS  Google Scholar 

  31. Gutiérrez-Pascual, E. et al. Direct pituitary effects of kisspeptin: activation of gonadotrophs and somatotrophs and stimulation of luteinising hormone and growth hormone secretion. J. Neuroendocrinol. 19, 521–530 (2007).

    Article  Google Scholar 

  32. Luquet, S., Perez, F.A., Hnasko, T.S. & Palmiter, R.D. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310, 683–685 (2005).

    Article  CAS  Google Scholar 

  33. Gropp, E. et al. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat. Neurosci. 8, 1289–1291 (2005).

    Article  CAS  Google Scholar 

  34. Bewick, G.A. et al. Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J. 19, 1680–1682 (2005).

    Article  CAS  Google Scholar 

  35. Chan, Y.M., Broder-Fingert, S., Wong, K.M. & Seminara, S.B. Kisspeptin/Gpr54-independent gonadotrophin-releasing hormone activity in Kiss1 and Gpr54 mutant mice. J. Neuroendocrinol. 21, 1015–1023 (2009).

    Article  CAS  Google Scholar 

  36. Boehm, U., Zou, Z. & Buck, L.B. Feedback loops link odor and pheromone signaling with reproduction. Cell 123, 683–695 (2005).

    Article  CAS  Google Scholar 

  37. Cravo, R.M. et al. Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience 173, 37–56 (2011).

    Article  CAS  Google Scholar 

  38. Navarro, V.M. et al. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J. Neurosci. 29, 11859–11866 (2009).

    Article  CAS  Google Scholar 

  39. Gibson, M.J. et al. Mating and pregnancy can occur in genetically hypogonadal mice with preoptic area brain grafts. Science 225, 949–951 (1984).

    Article  CAS  Google Scholar 

  40. Herbison, A.E., Porteous, R., Pape, J.R., Mora, J.M. & Hurst, P.R. Gonadotropin-releasing hormone neuron requirements for puberty, ovulation, and fertility. Endocrinology 149, 597–604 (2008).

    Article  CAS  Google Scholar 

  41. Gottsch, M.L. et al. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 145, 4073–4077 (2004).

    Article  CAS  Google Scholar 

  42. Navarro, V.M. et al. Effects of KiSS-1 peptide, the natural ligand of GPR54, on follicle-stimulating hormone secretion in the rat. Endocrinology 146, 1689–1697 (2005).

    Article  CAS  Google Scholar 

  43. Li, X.F. et al. Kisspeptin signalling in the hypothalamic arcuate nucleus regulates GnRH pulse generator frequency in the rat. PLoS ONE 4, e8334 (2009).

    Article  Google Scholar 

  44. Eggan, K. et al. Mice cloned from olfactory sensory neurons. Nature 428, 44–49 (2004).

    Article  CAS  Google Scholar 

  45. Rodríguez, C.I. et al. High-efficiency deleter mice show that FLPe is an alternative to Cre-loxP. Nat. Genet. 25, 139–140 (2000).

    Article  Google Scholar 

  46. Paxinos, G. & Franklin, K.B.J. The Mouse Brain in Stereotaxic Coordinates (Elsevier Academic Press, St. Louis, 2001).

Download references

Acknowledgements

We are indebted to O. Pongs for continuous support. A. Marquardt and D. Drexler provided expert technical assistance. We thank R. Kühn for providing the IGD3.2 embryonic stem cells and A. Waisman for providing the R26-iDTR mice, I. Hermans-Borgmeyer for help with embryonic stem cell work and blastocyst injections, A. Derin and U. Wolters for animal caretaking, B. Mann for performing the hormone assays and M. Roberson and K. Duncan for helpful discussions. This project was supported by Deutsche Forschungsgemeinschaft grant BO1743/2 to U.B.

Author information

Authors and Affiliations

Authors

Contributions

C.M. and U.B. designed the experiments. C.M. carried out most of the experiments. C.M. and U.B. analyzed the data. U.B. conceived the project and wrote the paper.

Corresponding author

Correspondence to Ulrich Boehm.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 1385 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mayer, C., Boehm, U. Female reproductive maturation in the absence of kisspeptin/GPR54 signaling. Nat Neurosci 14, 704–710 (2011). https://doi.org/10.1038/nn.2818

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2818

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing