Olfactory receptors are encoded by a family of 1,000 or more genes in mice. An olfactory sensory neuron expresses most likely only one of these genes. Neurons expressing a given receptor are scattered within one of four zones in the olfactory epithelium; the biological significance of the zonal pattern remains unknown. Axons of neurons expressing a given olfactory receptor project to two out of 1,800 glomeruli in the olfactory bulb, posing a formidable wiring problem. Previous studies by the sponsor have implicated the olfactory receptor itself in connectivity, but it cannot be the only determinant in the guidance process. In preliminary studies the applicant has focused on the M71 and M72 genes, which encode two highly related receptors that are expressed in the same epithelial zone. The M71 and M72 glomeruli were shown to be distinct. Here, a continuation of these experiments is proposed that seeks to define and describe two determinants of connectivity in the olfactory system: the epithelial zone in which the neurons are located, and the olfactory receptor itself. Gene targeting technology will be used to engineer mice such that they express a variety of knock-in mutations, mostly in the M71 gene. The experiments differ from previous studies by the sponsor in that genetic manipulation is carried out with olfactory receptor genes that are expressed in the same zone.
