DEVELOPMENT AND FUNCTION OF THE MAMMALIAN OLFACTORY SYSTEM

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The research goals of the Section of Molecular Neurobiology are to define the molecular mechanisms underlying the development and function of the mammalian olfactory system. One area of emphasis is the identification of molecules which direct the establishment of the precise patterns of synaptic connectivity observed between peripheral sensory neurons and their target neurons in the olfactory bulb. Unlike other sensory systems, there is little topographic organization of incoming olfactory sensory information within the periphery. However, within the olfactory bulb of the brain, there is a precise spatial representation of olfactory information with neurons expressing the same odorant receptor projecting their axons to the same secondary neurons. The molecular mechanisms mediating this convergence of axons of neurons expressing the same receptor type are not known. It has been hypothesized that the odorant receptors themselves may be involved in this process and thus play dual roles in both odorant recognition and axonal guidance. Full length cDNA clones of several odorant receptors have been isolated and cloned into mammalian and insect expression vectors, and heterologous cell expression systems are being developed. Such cell lines should facilitate the functional characterization of odorant receptors with respect to both ligand specificity and putative interactions with bulbar positional cues. In addition, members of several different gene families which have been implicated in axonal guidance in other systems are being evaluated for similar roles within the olfactory system. The major outcome of these studies has been the isolation of a novel member of the semaphorin gene family. Several members of the semaphorin gene family have been demonstrated to function in vitro as axonal guidance molecules, and mice deficient in semaD, one class IV member of the family, display defects in the patterning of specific axonal projections. Sema4g encodes a novel class IV member of the semaphorin gene family located on mouse chromosome 19. Like other class IV semaphorin genes, Sema4G is an integral membrane protein with characteristic semaphorin and extracellular Ig-homology domains. It is robustly expressed in both olfactory sensory neurons and their synaptic partners in the olfactory bulb during the time when axonal outgrowth and synaptogenesis are occurring. Embryonic expression of sema4g is also observed in the neuroepithelia of the vomeronasal organ, retina, and cochlea suggesting an important role for Sema4G in the development of these sensory systems. - olfactory system, axonal guidance, in situ hybridization, odorant receptors, semaphorin"