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）的嗅觉感觉神经元（OSN）将其轴突（OR）融合到嗅球中的一组特定的肾小球。1）我们表明，环状腺苷单磷酸腺苷（CAMP）的信号对轴突引导的表达对轴突的表达是对轴突的必不可少的。 ORS，刺激G蛋白，cAMP依赖性蛋白激酶和cAMP反应元件结合蛋白的遗传操纵沿嗅球前轴轴心移动了轴突投影位点。因此，确定OSN的目标目的地的是或不是直接作用或分子的直接作用。使用大多数OSN表达特定的转基因小鼠，或者，我们确定了编码均质粘合剂分子Kirrel2/kirrel3和排斥分子以ephrin-a5/epha5的基因。在CNGA2基因敲除小鼠中，诱发的阳离子膨胀被破坏，Kirrel2和Epha5被下调，而Kirrel3和Ephrin-A5上调，表明这些基因以活性依赖性方式转录。马赛克分析表明，这些基因的功能增益会产生重复的肾小球。我们建议一组特定的粘合剂/排斥分子，其表达水平由或分子确定，在肾小球图形成过程中调节OSN的轴突筋膜。