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

在小鼠中，表达相同气味受体（OR）的嗅觉感觉神经元（OSNs）将其轴突聚集到嗅球中的一组特定肾小球。1)我们发现调节轴突引导分子表达的环腺苷单磷酸（cAMP）信号对or指示轴突投射至关重要。ORs、刺激性G蛋白、cAMP依赖性蛋白激酶和cAMP反应元件结合蛋白的基因操作使嗅球内沿前后轴的轴突投射位点发生移位。因此，是OR衍生的cAMP信号，而不是OR分子的直接作用，决定了OSNs的目标目的地。2)为了研究or1指示的轴突束化是如何被控制的，我们寻找了表达谱与or1表达相关的基因。在大多数OSNs表达特定OR的转基因小鼠中，我们鉴定出这些基因编码亲同性粘附分子Kirrel2/Kirrel3和排斥分子ephrin-A5/EphA5。在CNGA2敲除小鼠中，气味诱发的阳离子内流被破坏，Kirrel2和EphA5下调，而Kirrel3和ephrin-A5上调，表明这些基因以活性依赖的方式转录。镶嵌分析表明，这些基因功能的增加产生了重复的肾小球。我们认为，在肾小球图形成过程中，一组特定的粘附/排斥分子（其表达水平由OR分子决定）调节了OSNs的轴突束化。

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.