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Identification of protein pheromones that promote aggressive behaviour


Mice use pheromones, compounds emitted and detected by members of the same species, as cues to regulate social behaviours such as pup suckling, aggression and mating1. Neurons that detect pheromones are thought to reside in at least two separate organs within the nasal cavity: the vomeronasal organ (VNO) and the main olfactory epithelium (MOE)2. Each pheromone ligand is thought to activate a dedicated subset of these sensory neurons. However, the nature of the pheromone cues and the identity of the responding neurons that regulate specific social behaviours are largely unknown. Here we show, by direct activation of sensory neurons and analysis of behaviour, that at least two chemically distinct ligands are sufficient to promote male–male aggression and stimulate VNO neurons. We have purified and analysed one of these classes of ligand and found its specific aggression-promoting activity to be dependent on the presence of the protein component of the major urinary protein (MUP) complex, which is known to comprise specialized lipocalin proteins bound to small organic molecules1,3,4. Using calcium imaging of dissociated vomeronasal neurons (VNs), we have determined that the MUP protein activates a sensory neuron subfamily characterized by the expression of the G-protein Gαo subunit (also known as Gnao) and Vmn2r putative pheromone receptors (V2Rs). Genomic analysis indicates species-specific co-expansions of MUPs and V2Rs, as would be expected among pheromone-signalling components. Finally, we show that the aggressive behaviour induced by the MUPs occurs exclusively through VNO neuronal circuits. Our results substantiate the idea of MUP proteins as pheromone ligands that mediate male–male aggression through the accessory olfactory neural pathway.

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Figure 1: Male urine contains two aggression pheromones.
Figure 2: HMW aggression activity is dependent on MUPs.
Figure 3: MUPs activate a subset of VNs that express Gαo.
Figure 4: MUP activation is specific to VNs.


  1. Stowers, L. & Marton, T. What is a pheromone? Mammalian pheromones reconsidered. Neuron 46, 699–702 (2005)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  3. Cavaggioni, A. & Mucignat-Caretta, C. Major urinary proteins, α2U-globulins and aphrodisin. Biochim. Biophys. Acta 1482, 218–228 (2000)

    CAS  Article  PubMed  Google Scholar 

  4. Flower, D. R. The lipocalin protein family: structure and function. Biochem. J. 318, 1–14 (1996)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Mugford, R. A. & Nowell, N. W. Pheromones and their effect on aggression in mice. Nature 226, 967–968 (1970)

    ADS  CAS  Article  PubMed  Google Scholar 

  6. Stowers, L. et al. Loss of sex discrimination and male–male aggression in mice deficient for TRP2. Science 295, 1493–1500 (2002)

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  9. Shi, P. & Zhang, J. Comparative genomic analysis identifies an evolutionary shift of vomeronasal receptor gene repertoires in the vertebrate transition from water to land. Genome Res. 17, 166–174 (2007)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Schwende, F. J. et al. Urinary volatile constituents of the house mouse, Mus musculus, and their endocrine dependency. J. Chem. Ecol. 12, 277–296 (1986)

    CAS  Article  PubMed  Google Scholar 

  11. Hastie, N. D., Held, W. A. & Toole, J. J. Multiple genes coding for the androgen-regulated major urinary proteins of the mouse. Cell 17, 449–457 (1979)

    CAS  Article  PubMed  Google Scholar 

  12. Robertson, D. H. et al. Molecular heterogeneity of urinary proteins in wild house mouse populations. Rapid Commun. Mass Spectrom. 11, 786–790 (1997)

    ADS  CAS  Article  PubMed  Google Scholar 

  13. Timm, D. E. et al. Structural basis of pheromone binding to mouse major urinary protein (MUP-I). Protein Sci. 10, 997–1004 (2001)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Novotny, M., Harvey, S., Jemiolo, B. & Alberts, J. Synthetic pheromones that promote inter-male aggression in mice. Proc. Natl Acad. Sci. USA 82, 2059–2061 (1985)

    ADS  CAS  Article  PubMed  Google Scholar 

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

    ADS  CAS  Article  PubMed  Google Scholar 

  16. Hurst, J. L., Robertson, D. H. L., Tolladay, U. & Beynon, R. J. Proteins in urine scent marks of male house mice extend the longevity of olfactory signals. Anim. Behav. 55, 1289–1297 (1998)

    CAS  Article  PubMed  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  18. Xia, J. et al. Urinary pheromones promote ERK/Akt phosphorylation, regeneration and survival of vomeronasal (V2R) neurons. Eur. J. Neurosci. 24, 3333–3342 (2006)

    Article  PubMed  Google Scholar 

  19. 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)

    CAS  Article  PubMed  Google Scholar 

  20. Takigami, S., Mori, Y., Tanioka, Y. & Ichikawa, M. Morphological evidence for two types of mammalian vomeronasal system. Chem. Senses 29, 301–310 (2004)

    Article  PubMed  Google Scholar 

  21. Mandiyan, V. S., Coats, J. K. & Shah, N. M. Deficits in sexual and aggressive behaviors in Cnga2 mutant mice. Nature Neurosci. 8, 1660–1662 (2005)

    CAS  Article  Google Scholar 

  22. Wang, Z. et al. Pheromone detection in male mice depends on signaling through the type 3 adenylyl cyclase in the main olfactory epithelium. J. Neurosci. 26, 7375–7379 (2006)

    CAS  Article  PubMed  Google Scholar 

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

    ADS  CAS  Article  PubMed  Google Scholar 

  24. Lucas, P., Ukhanov, K., Leinders-Zufall, T. & Zufall, F. A diacylglycerol-gated cation channel in vomeronasal neuron dendrites is impaired in TRPC2 mutant mice: mechanism of pheromone transduction. Neuron 40, 551–561 (2003)

    CAS  Article  Google Scholar 

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We thank F. Papes, U. Mueller, A. Patapoutian, K. Baldwin and C. Zucker for discussions and critical reading of the manuscript. This work was supported by funding from the NIDCD, Pew Charitable Trust, Skaggs Institute, and Helen Dorris Foundation (to L.S.), a National Institute on Deafness and Other Communication Disorders (NIDCD) pre-doctoral fellowship (T.F.M.) and The Basque Government Post-Doctoral Research Fellowship (P.C.).

Author Contributions The behavioural analysis was performed by P.C., J.R.C. and L.S.; calcium imaging was done by P.C. and T.F.M.; and biochemical purification of MUPs by T.F.M. and advised by B.F.C. SBT synthesis was performed by A.S. and B.F.C.; construct preparation and immunostaining by P.C., T.F.M. and K.F.; and genomic analysis by D.W.L. All authors participated in data analysis and writing of the manuscript.

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Correspondence to Lisa Stowers.

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Supplementary Information

This file includes Supplementary Figures 1 -5 with Legends, Supplementary Methods and additional references. The Supplementary Figures show wide range different control experiments for the calcium imaging, dose response to urine in behavior (SFig1), MUP purification by FPLC (SFig2), validation of SBT displacement by GC/MS (FigS3), ISH for Gi and Go antibodies (FigS4), and a neighbor-joining tree of MUP-like proteins from some terrestrial vertebrates (FigS5). (PDF 575 kb)

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Chamero, P., Marton, T., Logan, D. et al. Identification of protein pheromones that promote aggressive behaviour. Nature 450, 899–902 (2007).

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