Molecular Genesis and Organization of Olfactory Transduction Components and Cilia

哺乳动物嗅觉系统中气味检测的显著灵敏度和特异性源于 由高度专业化的细胞和分子组成。存在于嗅觉纤毛中的GPCR 神经元激活导致电活动和感觉传导的传导级联 信息到大脑。嗅觉受体（OR）基因大家族的发现提供了 解释了单个嗅觉神经元的不同敏感性。OR的功能性表达 异源系统代表了定义气味识别的分子基础的机会， 在指导这些蛋白质的有效运输方面取得了一定的进展。然而，我们所知甚少 关于天然感觉神经元用来产生高度专门化的感觉纤毛的机制， 将关键成分定位于这些结构，包括转导蛋白和气味受体。我们 最近表明，在鞭毛内运输（IFT）组件中具有遗传缺陷的个体 系统表现出严重嗅觉缺陷，在该疾病的鼠模型中重现。这些 观察结果为检查体内系统中的一般转运过程提供了基础， 了解专门的膜蛋白是如何移动到细胞内的特定位置。 我们建议定义在感觉神经元中用于指导信号运输的分子装置 转导元件。嗅觉受体的进化和结构保守性使它们 独特地适合于分子分选和亚细胞定位的系统解剖。我们将利用 分子和功能的方法来可视化和阐明纤毛形成的动力学，或 分布和转导蛋白定位。这些实验将补充那些来自 通过提供关于天然环境中受体运输的信息进行体外分析。 这些实验为嗅觉感觉神经元的发育提供了新的见解， 组织特异性蛋白质向感觉细胞器的移位和神经元的建立 连通性。蛋白质运输到特定的细胞位置和特殊纤毛的发育 对哺乳动物中的许多细胞类型至关重要。我们的研究应该提供有关 人类感觉和纤毛依赖性细胞功能疾病的发病机制。

The remarkable sensitivity and specificity of odorant detection in the mammalian olfactory system derives from highly specialized cellular and molecular components. GPCRs present in the cilia of the olfactory neurons activate a transduction cascade leading to electrical activity and the propagation of sensory information to the brain. The discovery of a large family of olfactory receptor (OR) genes provided an explanation for the differential sensitivity of individual olfactory neurons. Functional expression of ORs in heterologous systems represent an opportunity to define the molecular basis of odorant recognition and has led to modest progress in directing the efficient trafficking of these proteins. However, we know very little about the mechanisms utilized by native sensory neurons to create the highly specialized sensory cilia and localize critical components, including transduction proteins and odorant receptors to these structures. We recently demonstrated that individuals with genetic defects in components of the intraflagellar transport (IFT) system display profound olfactory deficits that are recapitulated in murine models of this disease. These observations provide a foundation for examining the general process of transport in an in vivo system and understanding how specialized integral membrane proteins are moved to specific locations within the cell. We propose to define the molecular apparatus used in sensory neurons to direct the trafficking of signal transduction components. The evolution and structural conservation of olfactory receptors make them uniquely amenable to a systematic dissection of molecular sorting and subcellular localization. We will utilize molecular and functional approaches to visualize and elucidate the dynamics of cilia formation, OR distribution and transduction protein localization. These experiments will complement those derived from in vitro analysis by providing information on receptor trafficking in a native context. These experiments afford new insights into the development of olfactory sensory neurons, pathways for the translocation of tissue-specific proteins to sensory organelles and the establishment of neuronal connectivity. The trafficking of proteins to specific cellular locations and the development of specialized cilia is critical to many cell types in mammals. Our studies should provide valuable new information regarding the pathogenesis of human diseases of sensory perception and cilia-dependent cellular function.