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Sex-specific peptides from exocrine glands stimulate mouse vomeronasal sensory neurons

Nature volume 437, pages 898–901 (2005)Cite this article

Abstract

In mammals, social and reproductive behaviours are modulated by pheromones, which are chemical signals that convey information about sex and strain1,2. The vomeronasal organ, located at the base of the nasal septum, is responsible for mediating pheromone information in mice3,4,5,6,7,8,9. Two classes of putative pheromone receptor gene families, V1R and V2R, are expressed by vomeronasal sensory neurons in mutually segregated epithelial zones of the vomeronasal organ10,11,12,13,14. Although numerous studies have suggested that pheromones originate from urine15,16,17,18, direct recordings of behaving mice have shown that neuronal firing in the vomeronasal system is modulated by physical contact with the facial area19. Here we identify a male-specific 7-kDa peptide secreted from the extraorbital lacrimal gland. This peptide, which we named exocrine gland-secreting peptide 1 (ESP1), is encoded by a gene from a previously unrecognized large family clustered in proximity to the class I major histocompatibility complex (MHC) region. ESP1 is secreted from the eyes and is transferred to the female vomeronasal organ, where it stimulates V2R-expressing vomeronasal sensory neurons and elicits an electrical response. Our results indicate that mice respond to sex-specific peptides released from exocrine glands through the vomeronasal system during direct contact.

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Figure 1: Induction of c-Fos in VSNs by various stimulants.
Figure 2: Identification of V2R receptor genes expressed in c-Fos-positive VSNs.
Figure 3: Purification and identification of c-Fos-inducing peptides.
Figure 4: Analysis of genes encoding ESP1 and its homologues.

References

  1. Dulac, C. & Torello, A. T. Molecular detection of pheromone signals in mammals: from genes to behaviour. Nature Rev. Neurosci. 4, 551–562 (2003)

    Article  CAS  Google Scholar 

  2. Brennan, P. A. & Keverne, E. B. Something in the air? New insights into mammalian pheromones. Curr. Biol. 14, R81–R89 (2004)

    Article  CAS  PubMed  Google Scholar 

  3. Clancy, A. N., Coquelin, A., Macrides, F., Gorski, R. A. & Noble, E. P. Sexual behaviour and aggression in male mice: involvement of the vomeronasal system. J. Neurosci. 4, 2222–2229 (1984)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wysocki, C. J. & Lepri, J. J. Consequences of removing the vomeronasal organ. J. Steroid Biochem. Mol. Biol. 39, 661–669 (1991)

    Article  CAS  PubMed  Google Scholar 

  5. Meredith, M. Chronic recording of vomeronasal pump activation in awake behaving hamsters. Physiol. Behav. 56, 345–354 (1994)

    Article  CAS  PubMed  Google Scholar 

  6. Stowers, L., Holy, T. E., Meister, M., Dulac, C. & Koentges, G. Loss of sex discrimination and male-male aggression in mice deficient for TRP2. Science 295, 1493–1500 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Leypold, B. G. et al. Altered sexual and social behaviors in trp2 mutant mice. Proc. Natl Acad. Sci. USA 99, 6376–6381 (2002)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Loconto, J. et al. Functional expression of murine V2R pheromone receptors involves selective association with the M10 and M1 families of MHC class Ib molecules. Cell 112, 607–618 (2003)

    Article  CAS  PubMed  Google Scholar 

  9. Norlin, E. M., Gussing, F. & Berghard, A. Vomeronasal phenotype and behavioural alterations in Gαi2 mutant mice. Curr. Biol. 13, 1214–1219 (2003)

    Article  CAS  PubMed  Google Scholar 

  10. Dulac, C. & Axel, R. A novel family of genes encoding putative pheromone receptors in mammals. Cell 83, 195–206 (1995)

    Article  CAS  PubMed  Google Scholar 

  11. Berghard, A. & Buck, L. B. Sensory transduction in vomeronasal neurons: evidence for Gαo, Gαi2, and adenylyl cyclase II as major components of a pheromone signalling cascade. J. Neurosci. 16, 909–918 (1996)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Herrada, G. & Dulac, C. A novel family of putative pheromone receptors in mammals with a topographically organized and sexually dimorphic distribution. Cell 90, 763–773 (1997)

    Article  CAS  PubMed  Google Scholar 

  13. Matsunami, H. & Buck, L. B. A multigene family encoding a diverse array of putative pheromone receptors in mammals. Cell 90, 775–784 (1997)

    Article  CAS  PubMed  Google Scholar 

  14. Ryba, N. J. & Tirindelli, R. A new multigene family of putative pheromone receptors. Neuron 19, 371–379 (1997)

    Article  CAS  PubMed  Google Scholar 

  15. Krieger, J. et al. Selective activation of G protein subtypes in the vomeronasal organ upon stimulation with urine-derived compounds. J. Biol. Chem. 274, 4655–4662 (1999)

    Article  CAS  PubMed  Google Scholar 

  16. Leinders-Zufall, T. et al. Ultrasensitive pheromone detection by mammalian vomeronasal neurons. Nature 405, 792–796 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Hurst, J. L. et al. Individual recognition in mice mediated by major urinary proteins. Nature 414, 631–634 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Boschat, C. et al. Pheromone detection mediated by a V1r vomeronasal receptor. Nature Neurosci. 5, 1261–1262 (2002)

    Article  CAS  PubMed  Google Scholar 

  19. Luo, M., Fee, M. S. & Katz, L. C. Encoding pheromonal signals in the accessory olfactory bulb of behaving mice. Science 299, 1196–1201 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Halem, H. A., Cherry, J. A. & Baum, M. J. Vomeronasal neuroepithelium and forebrain Fos responses to male pheromones in male and female mice. J. Neurobiol. 39, 249–263 (1999)

    Article  CAS  PubMed  Google Scholar 

  21. Kumar, A., Dudley, C. A. & Moss, R. L. Functional dichotomy within the vomeronasal system: distinct zones of neuronal activity in the accessory olfactory bulb correlate with sex-specific behaviors. J. Neurosci. 19, RC32 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Halem, H. A., Baum, M. J. & Cherry, J. A. Sex difference and steroid modulation of pheromone-induced immediate early genes in the two zones of the mouse accessory olfactory system. J. Neurosci. 21, 2474–2480 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kimoto, H. & Touhara, K. Induction of c-Fos expression in mouse vomeronasal neurons by sex-specific non-volatile pheromone(s). Chem. Senses 30 (suppl. 1), i146–i147 (2005)

    Article  CAS  PubMed  Google Scholar 

  24. Ishii, T., Hirota, J. & Mombaerts, P. Combinatorial coexpression of neural and immune multigene families in mouse vomeronasal sensory neurons. Curr. Biol. 13, 394–400 (2003)

    Article  CAS  PubMed  Google Scholar 

  25. Kikuyama, S. et al. Sodefrin: a female-attracting peptide pheromone in newt cloacal glands. Science 267, 1643–1645 (1995)

    Article  ADS  CAS  PubMed  Google Scholar 

  26. Wabnitz, P. A., Bowie, J. H., Tyler, M. J., Wallace, J. C. & Smith, B. P. Aquatic sex pheromone from a male tree frog. Nature 401, 444–445 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  27. Feldhoff, R. C., Rollmann, S. M. & Houck, L. D. in Advances in Chemical Signals in Vertebrates 117–25 (Kluwer-Plenum, New York, 1999)

    Book  Google Scholar 

  28. Rollmann, S. M., Houck, L. D. & Feldhoff, R. C. Proteinaceous pheromone affecting female receptivity in a terrestrial salamander. Science 285, 1907–1909 (1999)

    Article  CAS  PubMed  Google Scholar 

  29. Leinders-Zufall, T. et al. MHC class I peptides as chemosensory signals in the vomeronasal organ. Science 306, 1033–1037 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank K. Yamamoto for helping protein sequence analysis, K. Mori for providing DHB and SBT, and S. Sakuda and H. Kataoka for discussions. This work was supported in part by grants from the Japan Society for the Promotion of Science (JSPS) and the Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN) of Japan.

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Authors and Affiliations

  1. Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, 277-8562, Chiba, Japan

    Hiroko Kimoto, Sachiko Haga, Koji Sato & Kazushige Touhara

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  1. Hiroko Kimoto
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  2. Sachiko Haga
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  4. Kazushige Touhara
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Corresponding author

Correspondence to Kazushige Touhara.

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Competing interests

cDNA sequences have been deposited in GenBank under accession numbers AB194091 (ESP1), AB194093 (V2Rp1), AB194094 (V2Rp2) and AB194095 (V2Ro). Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Confocal microscopic analysis of c-Fos-positive neurons. (PDF 3235 kb)

Supplementary Figure 2

Source of a stimulant(s) from BALB/c adult male mice. (PDF 396 kb)

Supplementary Figure 3

Structural and functional analysis of purified peptides. (PDF 483 kb)

Supplementary Figure Legends

Text to accompany Supplementary Figures S1–S3. (DOC 26 kb)

Supplementary Methods

Additional details of the methods used in this study. (DOC 24 kb)

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Kimoto, H., Haga, S., Sato, K. et al. Sex-specific peptides from exocrine glands stimulate mouse vomeronasal sensory neurons. Nature 437, 898–901 (2005). https://doi.org/10.1038/nature04033

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