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

Abstract

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.

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Figure 1: Induction of c-Fos in VSNs by various stimulants.
Figure 2: Identification of V2R receptor genes expressed in c-Fos-positive VSNs.
Figure 3: Purification and identification of c-Fos-inducing peptides.
Figure 4: Analysis of genes encoding ESP1 and its homologues.

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Acknowledgements

We thank K. Yamamoto for helping protein sequence analysis, K. Mori for providing DHB and SBT, and S. Sakuda and H. Kataoka for discussions. This work was supported in part by grants from the Japan Society for the Promotion of Science (JSPS) and the Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN) of Japan.

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Correspondence to Kazushige Touhara.

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Competing interests

cDNA sequences have been deposited in GenBank under accession numbers AB194091 (ESP1), AB194093 (V2Rp1), AB194094 (V2Rp2) and AB194095 (V2Ro). Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Confocal microscopic analysis of c-Fos-positive neurons. (PDF 3235 kb)

Supplementary Figure 2

Source of a stimulant(s) from BALB/c adult male mice. (PDF 396 kb)

Supplementary Figure 3

Structural and functional analysis of purified peptides. (PDF 483 kb)

Supplementary Figure Legends

Text to accompany Supplementary Figures S1–S3. (DOC 26 kb)

Supplementary Methods

Additional details of the methods used in this study. (DOC 24 kb)

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Kimoto, H., Haga, S., Sato, K. et al. Sex-specific peptides from exocrine glands stimulate mouse vomeronasal sensory neurons. Nature 437, 898–901 (2005). https://doi.org/10.1038/nature04033

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