Sex-specific peptides from exocrine glands stimulate mouse vomeronasal sensory neurons

In mammals, social and reproductive behaviours are modulated by pheromones, which are chemical signals that convey information about sex and strain(1,2). The vomeronasal organ, located at the base of the nasal septum, is responsible for mediating pheromone information in mice(3-9). Two classes of putative pheromone receptor gene families, V1R and V2R, are expressed by vomeronasal sensory neurons in mutually segregated epithelial zones of the vomeronasal organ(10-14). Although numerous studies have suggested that pheromones originate from urine(15-18), direct recordings of behaving mice have shown that neuronal firing in the vomeronasal system is modulated by physical contact with the facial area(19). Here we identify a male-specific 7-kDa peptide secreted from the extraorbital lacrimal gland. This peptide, which we named exocrine gland-secreting peptide 1 (ESP1), is encoded by a gene from a previously unrecognized large family clustered in proximity to the class I major histocompatibility complex (MHC) region. ESP1 is secreted from the eyes and is transferred to the female vomeronasal organ, where it stimulates V2R-expressing vomeronasal sensory neurons and elicits an electrical response. Our results indicate that mice respond to sex-specific peptides released from exocrine glands through the vomeronasal system during direct contact.