The detection of chemosensory stimuli by the sensory neurons of the mouse vomeronasal organ (VNO) is mainly mediated by seven-transmembrane receptors that are encoded by two large gene repertoires, V1R and V2R. The mouse genome contains 122 intact V2R genes, which can be grouped in four families by sequence homology: families A, B, and D (115 genes), and family C (7 genes). Vomeronasal sensory neurons (VSNs) in the basal layer of the VNO epithelium coexpress two V2R genes in non-random combinations: one family-ABD V2R gene together with one family-C V2R gene, such as Vmn2r1 (29% of basal VSNs) or Vmn2r2 (52%). This coordinated coexpression may contribute to the highly specialized sensory response profiles of VSNs, for instance by heterodimerization of a family-ABD with a family-C V2R. The mechanisms that regulate this coordinated cooexpression of two V2R genes per basal VSN are not understood. Among possible models are a sequential and dependent model of expression; a model of random combinations of expression followed by cellular selection of VSNs with appropriate combinations; and a model of direct coordination of gene expression by another gene family such as genes encoding transcription factors. Here, we describe two novel mouse strains with targeted mutations in the family-ABD V2R gene V2rf2 that begin to provide insight into this problem. We observe that the great majority of VSNs that express intact V2rf2 coexpress Vmn2r1 immunoreactivity, and that the percentage of Vmn2r1 coexpression increases from 3 to 10wk. Having established this tight coexpression of V2rf2 with Vmn2r1, we then asked if it is maintained when the coding sequence of V2rf2 is deleted. We find that the number of VSNs expressing a locus with a targeted deletion in the coding sequence of V2rf2 that is likely a null mutation, is similar to the number of VSNs that express intact V2rf2. But 25% of these VSNs coexpress another family-ABD V2R, which is consistent with the absence of negative feedback from the mutated V2rf2 locus. Interestingly, 9.5% of VSNs expressing the targeted deletion of V2rf2 now coexpress Vmn2r2. Finally, the marginal region of the VNO epithelium, where immature VSNs are concentrated, has more RNA of family-ABD V2R genes than of family-C genes in postnatal wild-type mice. Our results are most consistent with the sequential and dependent model for the coordinated coexpression of two V2R genes per basal VSN.
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