Letter

Nature 450, 899-902 (6 December 2007) | doi:10.1038/nature05997; Received 26 July 2007; Accepted 12 October 2007

Identification of protein pheromones that promote aggressive behaviour

Pablo Chamero1,4, Tobias F. Marton1,4, Darren W. Logan1, Kelly Flanagan1, Jason R. Cruz1, Alan Saghatelian3, Benjamin F. Cravatt2 & Lisa Stowers1

  1. Department of Cell Biology,
  2. Department of Chemistry, The Scripps Research Institute, La Jolla, California 92030, USA
  3. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA
  4. These authors contributed equally to this work.

Correspondence to: Lisa Stowers1 Correspondence and requests for materials should be addressed to L.S. (Email: stowers@scripps.edu).

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 Galphao 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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