Molecular mechanisms underlying the formation of functional olfactory neural pathways

本研究以小鼠和斑马鱼为模型生物，试图阐明功能性嗅觉神经回路形成的分子和细胞机制，并获得以下重要发现：（1）我们证明了轴突导向分子Robo 2是斑马鱼嗅觉系统中精确的肾小球地图建立所必需的。在robo 2突变斑马鱼，误入歧途，早期生长的嗅觉轴突走错了路，往往渗透到间脑没有到达嗅球（OB）。此外，在成年OB的气味地图被扭曲的误入歧途的突变体。从这些结果，我们推测，最初的嗅觉轴突支架起着至关重要的作用，在确定地形肾小球地图在未来的OB。(2)We表明Arx同源盒基因和Fez锌指基因对小鼠嗅觉系统的发育是必需的。在胚胎发育过程中，Fez和Arx分别在嗅感觉神经元和OB中间神经元/放射状胶质细胞中表达。尽管不同的表达模式，Fez和Arx缺陷小鼠表现出相似的解剖表型，包括受损的神经支配的嗅觉轴突和异常的形态发生的OB。因此，嗅觉轴突投射和OB形成通过外周Fez和中央Arx的细胞自主功能相互依赖地发展。（3）分析了小鼠嗅球至嗅皮层的次级嗅觉通路中各种细胞识别分子的表达模式。我们发现外侧嗅束（LOT）发育过程中的层状结构，这反映了：1）从副嗅束和主嗅束分离的通路，2）二尖瓣细胞轴突的不同成熟度。结果表明，新生的未成熟轴突依次加入LOT最表层，形成具有不同成熟阶段的二尖瓣细胞轴突的堆积层。

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.