Molecular basis of specification and connectivity of sensory neurons in the olfactory system of Drosophila melanogaster

嗅觉系统通过从外围神经元到大脑高级中枢神经元的精确连线投射来区分大量的气味。对气味的反应能力在驱动重要行为方面起着重要作用。嗅觉受体神经元（ORN）表达特定的受体，而表达一类受体的神经元支配着大脑中称为肾小球的相同亚结构。果蝇的嗅觉系统显示出与哺乳动物嗅觉系统高度相似的组织结构。它的遗传易感性使其成为研究神经元身份和相应连接的惊人特异性是如何实现的理想模型。我未来的研究目标是了解ORN特异性和连通性如何在遗传上协调，并确定最终允许构建功能性神经网络的分子机制。可以想象，规范和连通性的协调是由ORN类特异性分子如转录因子提供的。我提出了两种主要方法来寻找这一过程中的关键调节因子：(1)之前从我的博士后工作中发现的突变体将被分析，这些突变体显示了神经元的特异性表型和惊人的连接突变体，(2)为了发现神经元特异性转录因子和控制类特异性连接的跨膜受体，候选基因组将使用抑制RNA的过表达来分析。在一个独立的方法中，直接跟进我之前的工作，FGF受体屏息在一个特定的ORN类中的功能将被表征。

The olfactory system discriminates between a large number of odorants using precisely wired projections from neurons in the periphery to neurons in higher brain centers. The ability to respond to an odor is instrumental in driving important behaviors. Olfactory receptor neurons (ORN) express specific receptors and neurons expressing one receptor class innervate the same substructures called glomeruli in the brain. The olfactory system of the fruitfly Drosophila melanogaster exhibits a highly similar organization to the mammalian olfactory system. Its genetic tractability makes it an ideal model to study how this striking specificity in neuron identity and corresponding wiring is achieved. My future research aims at understanding how ORN specificity and connectivity are coordinated genetically, and at identifying the molecular mechanisms that ultimately allow the construction of a functional neuronal network. It is conceivable that the ochestration of specification and connectivity is provided by ORN class specific molecules such as transcription factors. I am proposing two main approaches to find the critical regulators in this process: (1) previously identified mutants from my postdoctoral work showing neuron specification phenotypes and striking connectivity mutants will be analyzed, and (2) in order to discover the neuron-specific transcription factors and the transmembrane receptors that govern class specific wiring, candidate gene groups will be analyzed using overexpression of inhibitory RNA. In an independent approach directly following up my previous work, the function of the FGF receptor Breathless in one specific ORN class will be characterized.