UC San Diego

Mice use pheromones, chemical cues emitted in bodily secretions and detected by the olfactory system of conspecifics, to regulate important innate social behaviors, such as aggression and mating. 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), with each pheromone ligand activating a dedicated subset of these sensory neurons. Despite the molecular and anatomical characterization of these two olfactory pathways, little is understood about the identity of the pheromones that regulate critical behaviors, nor the identity of the sensory neurons that are activated to initiate a behavioral response. Urine is a rich source of pheromones, and male urine has been shown to be sufficient to generate intermale aggression in a VNO dependent manner (Stowers et al., 2002). Using direct activation of VNO sensory neurons (VNs) with behavioral analysis, this study identifies a novel family of genetically encoded pheromones, the Major Urinary Proteins (MUPs), which are sufficient to generate intermale aggression and activate VNs. MUPs are male-specific lipocalin proteins expressed in large quantities in urine that bind organic small molecules thought to be pheromones. This study shows that MUP activation of VNs is entirely protein dependent, in contrast to prior hypotheses that MUPs are merely passive carriers for their bioactive pheromone ligands. In addition, the VNs activated by MUPs are identified as the G[alpha]o, V2R pheromone receptor expressing class of neurons. Genomic analysis indicates species-specific co- expansions of MUPs and V2Rs, as would be expected among pheromone-signaling components. MUPs are expressed in unique strain and individual specific combinations of four to six of the 18 highly homologous MUP open reading frames arrayed on chromosome four. Here, we report that the VNO is tuned to discriminate between MUPs, despite the high homology in this gene family, indicating that the MUPs may activate a wide range of VNO sensory circuits, providing a rich source of information coding in the pheromone system. Finally, we have identified a discrete VNO sensory circuit activated by a single MUP that generates aggressive behavior. These findings are a fundamental step forward in elucidating the pheromone ligands that initiate important behaviors in mice, as well as understanding the neural circuitry that drives these critical social interactions