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Molecular basis of odorant receptor genes expression and axonal projection of olfactory sensory neurons

气味受体基因表达和嗅觉感觉神经元轴突投射的分子基础

基本信息

批准号：
14104026
负责人：
SAKANO Hitoshi
金额：
$ 72.88万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (S)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2006
项目状态：
已结题

项目摘要

In the mouse, olfactory sensory neurons (OSNs) expressing the same odorant receptor (OR) converge their axons to a specific set of glomeruli in the olfactory bulb.1)We show that cyclic adenosine monophosphate (cAMP) signals that regulate the expression of axon guidance molecules are essential for the OR-instructed axonal projection. Genetic manipulations of ORs, stimulatory G protein, cAMP-dependent protein kinase, and cAMP response element-binding protein shifted the axonal projection sites along the anteriorposterior axis in the olfactory bulb. Thus, it is the OR-derived cAMP signals, rather than direct action of OR molecules, that determine the target destinations of OSNs.2)To study how ORinstructed axonal fasciculation is controlled, we searched for genes whose expression profiles are correlated with the expressed ORs. Using the transgenic mouse in which the majority of OSNs express a particular OR, we identified such genes coding for the homophilic adhesive molecules Kirrel2/Kirrel3 and repulsive molecules ephrin-A5/EphA5. In the CNGA2 knockout mouse, where the odor-evoked cation influx is disrupted, Kirrel2 and EphA5 were downregulated, while Kirrel3 and ephrin-A5 were upregulated, indicating that these genes are transcribed in an activity-dependent manner. Mosaic analysis demonstrated that gain of function of these genes generates duplicated glomeruli. We propose that a specific set of adhesive/ repulsive molecules, whose expression levels are determined by OR molecules, regulate the axonal fasciculation of OSNs during the process of glomerular map formation.

在小鼠中，表达相同气味受体(OR)的嗅觉神经元(OSNs)将其轴突会聚到嗅球中的一组特定的肾小球1)我们证明了调节轴突引导分子表达的环磷酸腺苷(CAMP)信号对于OR指示的轴突投射是必不可少的。ORs、刺激性G蛋白、cAMP依赖的蛋白激酶和cAMP反应元件结合蛋白的基因操作使嗅球轴突投射位置沿前后轴移动。因此，是OR派生的cAMP信号，而不是OR分子的直接作用，决定了OSNs的靶向。2)为了研究OR指令的轴突震颤是如何控制的，我们寻找其表达谱与表达的OR相关的基因。利用大多数OSN表达特定OR的转基因小鼠，我们鉴定了编码同嗜性黏附分子Kirrel2/Kirrel3和排斥性分子ePhin-A5/EPHA5的基因。在CNGA2基因敲除小鼠中，气味诱发的阳离子内流被扰乱，Kirrel2和EPHA5下调，而Kirrel3和ewitin-A5上调，表明这些基因以活动依赖的方式转录。马赛克分析表明，这些基因功能的获得会产生重复的肾小球。我们认为，在肾小球MAP的形成过程中，一组特定的黏附/排斥分子的表达水平由OR分子决定，调节OSN的轴突颤动。