Nature 437, 898-901 (6 October 2005) | doi:10.1038/nature04033; Received 10 February 2005; Accepted 11 July 2005

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

Hiroko Kimoto1, Sachiko Haga1, Koji Sato1 & Kazushige Touhara1

  1. Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan

Correspondence to: Kazushige Touhara1 Correspondence and requests for materials should be addressed to K.T. (Email: touhara@k.u-tokyo.ac.jp). cDNA sequences have been deposited in GenBank under accession numbers AB194091 (ESP1), AB194093 (V2Rp1), AB194094 (V2Rp2) and AB194095 (V2Ro).

In mammals, social and reproductive behaviours are modulated by pheromones, which are chemical signals that convey information about sex and strain1, 2. The vomeronasal organ, located at the base of the nasal septum, is responsible for mediating pheromone information in mice3, 4, 5, 6, 7, 8, 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 organ10, 11, 12, 13, 14. Although numerous studies have suggested that pheromones originate from urine15, 16, 17, 18, direct recordings of behaving mice have shown that neuronal firing in the vomeronasal system is modulated by physical contact with the facial area19. 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.