Molecular mechanisms underlying the formation of functional olfactory neural pathways

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Using mice and zebrafish as model organisms, we attempted to elucidate the molecular and cellular mechanisms underlying the formation of functional olfactory neural circuitry and obtained several important findings as follows :(1)We demonstrated that an axon guidance molecule, Robo2, is required for establishment of a precise glomerular map in the zebrafish olfactory system. In robo2 mutant zebrafish, astray, early growing olfactory axons misrouted and often penetrated into the diencephalons without reaching the olfactory bulb (OB). Furthermose, the odor map in the adult OB was distorted in the astray mutants. From these results, we hypothesize that the initial olfactory axon scaffold plays an essential role in determining a topographic glomerular map in the future OB.(2)We demonstrated that Arx homeobox gene and Fez zinc finger gene are essential for development of mouse olfactory system. During embryonic development, Fez and Arx are expressed in the olfactory sensory neurons and in the OB interneurons/radial glia, respectively. In spite of the different expression patterns, Fez- and Arx-deficient mice show similar anatomical phenotypes including the impaired innervation of olfactory axons and the abnormal morphogenesis of OB. Thus, the olfactory axon projection and the OB formation develop interdependently through cell-autonomous functions of peripheral Fez and central Arx.(3)The expression patterns of various cell recognition molecules were analyzed in the secondary olfactory pathways from the OB to the olfactory cortex in mice. We discovered the laminar organization of developing lateral olfactory tract (LOT), which reflects : 1)the segregated pathways from the accessory and main OBs, and 2)the different maturity of mitral cell axons. The results suggest that newly generated immature axons are added to the most superficial lamina of LOT successively, leading to the formation of piled laminas with different maturational stages of the mitral cell axons.