Abstract
The vomeronasal organ (VNO) has a key role in mediating the social and defensive responses of many terrestrial vertebrates to species- and sex-specific chemosignals1. More than 250 putative pheromone receptors have been identified in the mouse VNO2,3, but the nature of the signals detected by individual VNO receptors has not yet been elucidated. To gain insight into the molecular logic of VNO detection leading to mating, aggression or defensive responses, we sought to uncover the response profiles of individual vomeronasal receptors to a wide range of animal cues. Here we describe the repertoire of behaviourally and physiologically relevant stimuli detected by a large number of individual vomeronasal receptors in mice, and define a global map of vomeronasal signal detection. We demonstrate that the two classes (V1R and V2R) of vomeronasal receptors use fundamentally different strategies to encode chemosensory information, and that distinct receptor subfamilies have evolved towards the specific recognition of certain animal groups or chemical structures. The association of large subsets of vomeronasal receptors with cognate, ethologically and physiologically relevant stimuli establishes the molecular foundation of vomeronasal information coding, and opens new avenues for further investigating the neural mechanisms underlying behaviour specificity.
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References
Dulac, C. & Torello, A. T. Molecular detection of pheromone signals in mammals: from genes to behaviour. Nature Rev. Neurosci. 4, 551–562 (2003)
Zhang, X., Marcucci, F. & Firestein, S. High-throughput microarray detection of vomeronasal receptor gene expression in rodents. Front. Neuroscience 4, 164 (2010)
Dulac, C. & Axel, R. A novel family of genes encoding putative pheromone receptors in mammals. Cell 83, 195–206 (1995)
Buck, L. & Axel, R. A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65, 175–187 (1991)
Papes, F., Logan, D. W. & Stowers, L. The vomeronasal organ mediates interspecies defensive behaviors through detection of protein pheromone homologs. Cell 141, 692–703 (2010)
Haga, S. et al. The male mouse pheromone ESP1 enhances female sexual receptive behaviour through a specific vomeronasal receptor. Nature 466, 118–122 (2010)
Leinders-Zufall, T., Ishii, T., Mombaerts, P., Zufall, F. & Boehm, T. Structural requirements for the activation of vomeronasal sensory neurons by MHC peptides. Nature Neurosci. 12, 1551–1558 (2009)
Boschat, C. et al. Pheromone detection mediated by a V1r vomeronasal receptor. Nature Neurosci. 5, 1261–1262 (2002)
He, J., Ma, L., Kim, S., Nakai, J. & Yu, C. R. Encoding gender and individual information in the mouse vomeronasal organ. Science 320, 535–538 (2008)
Leinders-Zufall, T. et al. Ultrasensitive pheromone detection by mammalian vomeronasal neurons. Nature 405, 792–796 (2000)
Holekamp, T. F., Turaga, D. & Holy, T. E. Fast three-dimensional fluorescence imaging of activity in neural populations by objective-coupled planar illumination microscopy. Neuron 57, 661–672 (2008)
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)
Ben-Shaul, Y., Katz, L. C., Mooney, R. & Dulac, C. In vivo vomeronasal stimulation reveals sensory encoding of conspecific and allospecific cues by the mouse accessory olfactory bulb. Proc. Natl Acad. Sci. USA 107, 5172–5177 (2010)
Berghard, A. & Buck, L. B. Sensory transduction in vomeronasal neurons: evidence for Gαo, Gαi2, and adenylyl cyclase II as major components of a pheromone signaling cascade. J. Neurosci. 16, 909–918 (1996)
Jia, C. & Halpern, M. Subclasses of vomeronasal receptor neurons: differential expression of G proteins (Gαi2 and Gαo) and segregated projections to the accessory olfactory bulb. Brain Res. 719, 117–128 (1996)
Tian, L. et al. Imaging neural activity in worms, flies and mice with improved GCaMP calcium indicators. Nature Methods 6, 875–881 (2009)
Martini, S., Silvotti, L., Shirazi, A., Ryba, N. J. & Tirindelli, R. Co-expression of putative pheromone receptors in the sensory neurons of the vomeronasal organ. J. Neurosci. 21, 843–848 (2001)
Stewart, R. & Lane, R. P. V1R promoters are well conserved and exhibit common putative regulatory motifs. BMC Genomics 8, 253 (2007)
Liberles, S. D. et al. Formyl peptide receptors are candidate chemosensory receptors in the vomeronasal organ. Proc. Natl Acad. Sci. USA 106, 9842–9847 (2009)
Rivière, S., Challet, L., Fluegge, D., Spehr, M. & Rodriguez, I. Formyl peptide receptor-like proteins are a novel family of vomeronasal chemosensors. Nature 459, 574–577 (2009)
Holy, T. E., Dulac, C. & Meister, M. Responses of vomeronasal neurons to natural stimuli. Science 289, 1569–1572 (2000)
Taha, M., McMillon, R., Napier, A. & Wekesa, K. S. Extracts from salivary glands stimulate aggression and inositol-1, 4, 5-triphosphate (IP3) production in the vomeronasal organ of mice. Physiol. Behav. 98, 147–155 (2009)
Samuelsen, C. L. & Meredith, M. The vomeronasal organ is required for the male mouse medial amygdala response to chemical-communication signals, as assessed by immediate early gene expression. Neuroscience 164, 1468–1476 (2009)
Brown, J., Kotler, B., Smith, R. & Wirtz, W. The effects of owl predation on the foraging behavior of heteromyid rodents. Oecologia 76, 408–415 (1988)
Sundell, J. et al. Variation in predation risk and vole feeding behaviour: a field test of the risk allocation hypothesis. Oecologia 139, 157–162 (2004)
Wagner, S., Gresser, A. L., Torello, A. T. & Dulac, C. A multireceptor genetic approach uncovers an ordered integration of VNO sensory inputs in the accessory olfactory bulb. Neuron 50, 697–709 (2006)
Chevret, P., Veyrunes, F. & Britton-Davidian, J. Molecular phylogeny of the genus Mus (Rodentia: Murinae) based on mitochondrial and nuclear data. Biol. J. Linn. Soc. 84, 417–427 (2005)
Guénet, J. L. & Bonhomme, F. Wild mice: an ever-increasing contribution to a popular mammalian model. Trends Genet. 19, 24–31 (2003)
Dulac, C. & Wagner, S. Genetic analysis of brain circuits underlying pheromone signaling. Annu. Rev. Genet. 40, 449–467 (2006)
Nodari, F. et al. Sulfated steroids as natural ligands of mouse pheromone-sensing neurons. J. Neurosci. 28, 6407–6418 (2008)
Miller, R. A. et al. Mouse (Mus musculus) stocks derived from tropical islands: new models for genetic analysis of life-history traits. J. Zool. 250, 95–104 (2000)
Schaeren-Wiemers, N. & Gerfin-Moser, A. A single protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: in situ hybridization using digoxigenin-labelled cRNA probes. Histochemistry 100, 431–440 (1993)
Danciger, E., Mettling, C., Vidal, M., Morris, R. & Margolis, F. Olfactory marker protein gene: its structure and olfactory neuron-specific expression in transgenic mice. Proc. Natl Acad. Sci. USA 86, 8565–8569 (1989)
Acknowledgements
We acknowledge H. Fisher, H. Hoekstra, E. Kay, M. Kirchgessner, N. Uchida, A. Wang, X.-D. Wang, B. Watson, W. Tong, Harvard Museum of Natural History, Harvard Concord Field Station, Museum of Science, Boston, and New England Wildlife Center, for providing stimulus materials used in this study, L. Looger for the G-CaMP3 construct, M. Wienisch, F. Markopoulos and D. Mak for help with electrophysiology and imaging experiments, and B. Goetze and the Harvard Center for Biological Imaging for help with microscopy. We also thank members of the Dulac laboratory for critical reading of the manuscript, S. Andreeva for technical support and R. Hellmiss for help with figure artwork. This work was supported by the NIDCD at the National Institute of Health, the Howard Hughes Medical Institute and the Damon Runyon Cancer Research Foundation (Y.I., DRG-1981-08).
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Y.I. and C.D. designed the study. Y.I., S.S. and T.T. designed and generated RNA probes, performed RNA in situ hybridization, and analysed data. L.P.-L. performed pilot experiments for data shown in Fig. 1 and produced recombinant ESP1. Y.I. and V.K. performed calcium imaging and electrophysiology. V.N.M. supervised physiology experiments. Y.I. and C.D. wrote the paper.
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The file contains Supplementary Figures 1-12 with legends and Supplementary Tables 1-2. (PDF 24866 kb)
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Isogai, Y., Si, S., Pont-Lezica, L. et al. Molecular organization of vomeronasal chemoreception. Nature 478, 241–245 (2011). https://doi.org/10.1038/nature10437
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DOI: https://doi.org/10.1038/nature10437
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