Deficient pheromone responses in mice lacking a cluster of vomeronasal receptor genes

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Abstract

The mammalian vomeronasal organ (VNO), a part of the olfactory system, detects pheromones—chemical signals that modulate social and reproductive behaviours1,2. But the molecular receptors in the VNO that detect these chemosensory stimuli remain undefined. Candidate pheromone receptors are encoded by two distinct and complex superfamilies of genes, V1r and V2r (refs 3 and 4), which code for receptors with seven transmembrane domains. These genes are selectively expressed in sensory neurons of the VNO. However, there is at present no functional evidence for a role of these genes in pheromone responses. Here, using chromosome engineering technology5, we delete in the germ line of mice a 600-kilobase genomic region that contains a cluster of 16 intact V1r genes6. These genes comprise two of the 12 described V1r gene families7, and represent 12% of the V1r repertoire. The mutant mice display deficits in a subset of VNO-dependent behaviours: the expression of male sexual behaviour and maternal aggression is substantially altered. Electrophysiologically, the epithelium of the VNO of such mice does not respond detectably to specific pheromonal ligands. The behavioural impairment and chemosensory deficit support a role of V1r receptors as pheromone receptors.

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Figure 1: Targeted deletion of a cluster of V1r genes.
Figure 2: ΔV1rabΔ females exhibit a reduced level of maternal aggression.
Figure 3: Behaviour of ΔV1rabΔ males.
Figure 4: Chemosensory deficits in ΔV1rabΔ mice.

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Acknowledgements

We thank R. Peraza and A. Walsh for producing chimaeric mice, D. Pfaff for fostering this collaboration, M. Novotny for providing 2,3-dehydro-exo-brevicomin and 6-hydroxy-6-methyl-3-heptanone, and T. Bozza, S. Firestein, C. Greer, K. Kelliher and D. Pfaff for critical reading of the manuscript. Postdoctoral fellowship support to I.R. was from the Swiss National Foundation for Research. Grant support to T.L-Z. and F.Z. was from NIH/NIDCD, and to P.M. from the March of Dimes Birth Defects Foundation.

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Correspondence to Peter Mombaerts.

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Del Punta, K., Leinders-Zufall, T., Rodriguez, I. et al. Deficient pheromone responses in mice lacking a cluster of vomeronasal receptor genes. Nature 419, 70–74 (2002) doi:10.1038/nature00955

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