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敏感性和特异性源于 来自高度专业化的细胞和分子成分。嗅觉纤毛中的GPCRs 神经元激活一个转导级联，导致电活动和感觉的传播 信息传给大脑。嗅觉受体(OR)基因大家族的发现提供了一种 对个体嗅觉神经元差异敏感性的解释。中OR的函数表达式 异源系统代表了定义气味识别的分子基础的机会，并具有 在指导这些蛋白质的有效贩运方面取得了一定的进展。然而，我们对此知之甚少 关于天然感觉神经元用来创造高度专门化的感觉纤毛和 定位关键成分，包括转导蛋白和气味受体到这些结构。我们 最近证明，在鞭毛内转运(IFT)组件中有遗传缺陷的个体 系统表现出严重的嗅觉缺陷，这在这种疾病的小鼠模型中得到了概括。这些 观察结果为研究体内系统的一般运输过程提供了基础 了解专门化的完整膜蛋白如何移动到细胞内的特定位置。 我们建议定义感觉神经元中用来指导信号传输的分子装置 转导组件。嗅觉感受器的进化和结构保守使它们 独特地服从对分子分类和亚细胞定位的系统剖析。我们将利用 分子和功能方法可视化和阐明纤毛形成的动力学，或 分布和转导蛋白的定位。这些实验将补充那些源自In的实验 通过提供有关本土背景下受体贩运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， 组织特异性蛋白向感觉细胞器的移位与神经元的建立 连通性。蛋白质向特定细胞位置的运输和特化纤毛的发育 对哺乳动物中的许多细胞类型都是至关重要的。我们的研究应该会提供关于 人类感觉和纤毛依赖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.