How the olfactory system discriminates among odorants is largely unknown. Physiological studies suggest that olfactory neurons with similar functional specificities project to the same glomerulus in the olfactory bulb. The convergence of 1000 or more widely dispersed neurons on a single glomerulus represents an impressive degree of sorting and targeting. What molecular cues guide growth cones to and within the bulb? To identify these signals, the zebrafish embryo will be used as a model system because of its anatomical simplicity and optical clarity. Two simple screens, using either a monoclonal antibody or an RNA in situ hybridization technique, will be employed to search for molecules whose expression is restricted to subsets of the bulb, the nasal epithelium, and/or the axons during development. These potential pathfinding or targeting candidates will be isolated, and functionally tested in general misexpression experiments. One highly promising putative targeting molecule has already been identified in human and chick. When mutant, this gene results in Kallmann's Syndrome, a defect characterized by anosmia due to a failure of olfactory neurons to innervate the bulb. This proposal will attempt to clone the zebrafish homolog in order to study it in this anatomically simple system.
