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.

  • Letter
  • Published:

Deficient pheromone responses in mice lacking a cluster of vomeronasal receptor genes

Abstract

The mammalian vomeronasal organ (VNO), a part of the olfactory system, detects pheromones—chemical signals that modulate social and reproductive behaviours1,2. But the molecular receptors in the VNO that detect these chemosensory stimuli remain undefined. Candidate pheromone receptors are encoded by two distinct and complex superfamilies of genes, V1r and V2r (refs 3 and 4), which code for receptors with seven transmembrane domains. These genes are selectively expressed in sensory neurons of the VNO. However, there is at present no functional evidence for a role of these genes in pheromone responses. Here, using chromosome engineering technology5, we delete in the germ line of mice a 600-kilobase genomic region that contains a cluster of 16 intact V1r genes6. These genes comprise two of the 12 described V1r gene families7, and represent 12% of the V1r repertoire. The mutant mice display deficits in a subset of VNO-dependent behaviours: the expression of male sexual behaviour and maternal aggression is substantially altered. Electrophysiologically, the epithelium of the VNO of such mice does not respond detectably to specific pheromonal ligands. The behavioural impairment and chemosensory deficit support a role of V1r receptors as pheromone receptors.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Targeted deletion of a cluster of V1r genes.
Figure 2: ΔV1rabΔ females exhibit a reduced level of maternal aggression.
Figure 3: Behaviour of ΔV1rabΔ males.
Figure 4: Chemosensory deficits in ΔV1rabΔ mice.

Similar content being viewed by others

References

  1. Halpern, M. The organisation and function of the vomeronasal system. Annu. Rev. Neurosci. 10, 325–362 (1987)

    Article  CAS  Google Scholar 

  2. Keverne, E. B. The vomeronasal organ. Science 286, 716–720 (1999)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Tirindelli, R., Mucignat-Caretta, C. & Ryba, N. J. Molecular aspects of pheromonal communication via the vomeronasal organ of mammals. Trends Neurosci. 21, 482–486 (1998)

    Article  CAS  Google Scholar 

  5. Ramirez-Solis, R., Liu, P. & Bradley, A. Chromosome engineering in mice. Nature 378, 720–724 (1995)

    Article  ADS  CAS  Google Scholar 

  6. Del Punta, K., Rothman, A., Rodriguez, I. & Mombaerts, P. Sequence diversity and genomic organization of vomeronasal receptor genes in the mouse. Genome Res. 10, 1958–1967 (2000)

    Article  CAS  Google Scholar 

  7. Rodriguez, I., Del Punta, K., Rothman, A., Ishii, T. & Mombaerts, P. Multiple new and isolated families within the mouse superfamily of V1r vomeronasal receptors. Nature Neurosci. 5, 134–139 (2002)

    Article  CAS  Google Scholar 

  8. Holy, T. E., Dulac, C. & Meister, M. Responses of vomeronasal neurons to natural stimuli. Science 289, 1569–1572 (2000)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  10. Sam, M. et al. Odorants may arouse instinctive behaviours. Nature 412, 142 (2001)

    Article  ADS  CAS  Google Scholar 

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

    Article  Google Scholar 

  12. Lane, R. P., Cutforth, T., Axel, R., Hood, L. & Trask, B. J. Sequence analysis of mouse vomeronasal receptor gene clusters reveals common promoter motifs and a history of recent expansion. Proc. Natl Acad. Sci. USA 99, 291–296 (2002)

    Article  ADS  CAS  Google Scholar 

  13. Bean, N. J. & Wysocki, C. J. Vomeronasal organ removal and female mouse aggression: the role of experience. Physiol. Behav. 45, 875–882 (1989)

    Article  CAS  Google Scholar 

  14. Bean, N. J. Olfactory and vomeronasal mediation of ultrasonic vocalizations in male mice. Physiol. Behav. 28, 31–37 (1982)

    Article  CAS  Google Scholar 

  15. Wysocki, C. J., Nyby, J., Whitney, G., Beauchamp, G. K. & Katz, Y. The vomeronasal organ: primary role in mouse chemosensory gender recognition. Physiol. Behav. 29, 315–327 (1982)

    Article  CAS  Google Scholar 

  16. Bean, N. J. Modulation of agonistic behavior by the dual olfactory system in male mice. Physiol. Behav. 29, 433–437 (1982)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Ogawa, S. et al. Abolition of male sexual behaviors in mice lacking estrogen receptors α and β (αβERKO). Proc. Natl Acad. Sci. USA 97, 14737–14741 (2000)

    Article  ADS  CAS  Google Scholar 

  19. Amoore, J. E. & Steinle, S. in Chemical Senses Vol. 3, Genetics of Perception and Communication (eds Wysocki, C. J. & Klare, M. R.) 331–351 (Marcel Dekker, New York, 1991)

    Google Scholar 

  20. Takigami, S. et al. The expressed localisation of rat putative pheromone receptors. Neurosci. Lett. 272, 115–118 (1999)

    Article  CAS  Google Scholar 

  21. Belluscio, L., Koentges, G., Axel, R. & Dulac, C. A map of pheromone receptor activation in the mammalian brain. Cell 97, 209–220 (1999)

    Article  CAS  Google Scholar 

  22. Rodriguez, I., Feinstein, P. & Mombaerts, P. Variable patterns of axonal projections of sensory neurons in the mouse vomeronasal system. Cell 97, 199–208 (1999)

    Article  CAS  Google Scholar 

  23. Mombaerts, P. Seven-transmembrane proteins as odorant and chemosensory receptors. Science 286, 707–711 (1999)

    Article  CAS  Google Scholar 

  24. Firestein, S. How the olfactory system makes sense of scents. Nature 413, 211–218 (2001)

    Article  ADS  CAS  Google Scholar 

  25. Slotnick, B. & Bodyak, N. Odor discrimination and odor quality perception in rats with disruption of connections between the olfactory epithelium and olfactory bulbs. J. Neurosci. 22, 4205–4216 (2002)

    Article  CAS  Google Scholar 

  26. Hildebrand, J. G. Analysis of chemical signals by nervous systems. Proc. Natl Acad. Sci. USA 92, 67–74 (1995)

    Article  ADS  CAS  Google Scholar 

  27. Sorensen, P. W., Christensen, T. A. & Stacey, N. E. Discrimination of pheromonal cues in fish: emerging parallels with insects. Curr. Opin. Neurobiol. 8, 458–467 (1998)

    Article  CAS  Google Scholar 

  28. 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  Google Scholar 

  29. 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  Google Scholar 

  30. Matzuk, M. M., Finegold, M. J., Su, J. G., Hsueh, A. J. & Bradley, A. Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice. Nature 360, 313–319 (1992)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Peraza and A. Walsh for producing chimaeric mice, D. Pfaff for fostering this collaboration, M. Novotny for providing 2,3-dehydro-exo-brevicomin and 6-hydroxy-6-methyl-3-heptanone, and T. Bozza, S. Firestein, C. Greer, K. Kelliher and D. Pfaff for critical reading of the manuscript. Postdoctoral fellowship support to I.R. was from the Swiss National Foundation for Research. Grant support to T.L-Z. and F.Z. was from NIH/NIDCD, and to P.M. from the March of Dimes Birth Defects Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peter Mombaerts.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Del Punta, K., Leinders-Zufall, T., Rodriguez, I. et al. Deficient pheromone responses in mice lacking a cluster of vomeronasal receptor genes. Nature 419, 70–74 (2002). https://doi.org/10.1038/nature00955

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature00955

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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