The vomeronasal organ (VNO) is a chemosensory organ specialized in the detection of pheromones in higher vertebrates. In mouse and rat, two gene super families, V1r and V2r vomeronasal receptor genes, are expressed in sensory neurons whose cell bodies are located in, respectively, the apical and basal layers of the VNO epithelium. We and others have reported that neurons of the basal layer express another multigene family, termed H2-Mv, representing nonclassical class I genes of the major histocompatibility complex (Mhc). The nine H2-Mv genes are expressed differentially in subsets of neurons and more than one H2-Mv gene can be expressed in an individual neuron. V2rs and H2-Mvs molecules are co-expressed in preferred combinations. H2-Mvs appear to function as escort molecules in transport of V2rs to the cell surface. The functions of the V2r and H2-Mv complex on the cell surface, and the significance of the combinatorial coexpression of V2r and H2-Mv is not known. I propose to produce strains of mice with targeted mutations in the H2-Mv locus and in V2r genes. Specific Aim 1 is to elucidate the in vivo function of the H2-Mv gene family by deleting the cluster containing all known H2-Mv genes by the technique of chromosome engineering. Axonal projections of vomeronasal sensory neurons, electrophysiological properties, and sexual and social behaviors will be analyzed. Specific Aim 2 is to understand the mechanism and significance of variegated expression of H2-Mv coupled with V2r expression by a targeted integration of IRES-taulacZ or IRES-tauGFP cassette into individual H2-Mv and V2r genes. The wiring patterns between the vomeronasal epithelium and the brain will be visualized, and functions of H2-Mv and V2r proteins in the axon targeting and combinatorial coexpression will be tested. This study will reveal not only novel functions of the nonclassical molecules of Mhc class I, but will provide new insights into parallels between the nervous and immune systems.