痕量胺相关受体新型嗅觉子系统的功能和发育机制

Olfaction is the primary sense used by most animals to perceive the external world. Detection of odorants and pheromones by the olfactory system allows animals to perform key behaviors relevant for survival, such as mating, foraging, and escaping from predators. The mouse olfactory system is comprised of several sensory structures, the largest of which is the main olfactory epithelium (MOE). Olfactory sensory neurons (OSNs) located within the MOE detect odors and pheromones using dedicated seven transmembrane, G protein-coupled receptors (GPCRs). Two families of GPCRs are expressed in the MOE and are conserved in humans and other vertebrates: odorant receptors (ORs), which are encoded by the largest gene family in mammals, and trace amine-associated receptors (TAARs), a smaller family of GPCRs distantly related to biogenic amine receptors. Several TAARs detect volatile amines including ethological odors that evoke innate animal behavioral responses. Mouse TAAR4 recognizes the aversive predator odor 2-phenylethylamine, while mouse TAAR5 detects the attractive male mouse odor trimethylamine. In zebrafish, TAAR13c detects the foul death-associated odor cadaverine and mediates innate avoidance behavior. Furthermore, human TAAR5 also recognizes trimethylamine, which is produced in extremely high level in patients with genetic disease ‘fish malodor syndrome’ and is strongly repulsive to human. Thus, TAAR olfactory subsystem provides an excellent model for mechanistic study of odor valence encoding. Here, we intend to investigate multiple aspects of the TAAR subsystem, including receptor deorphanization, structural basis of ligand recognition, olfactory circuits, animal behavioral responses, and mechanisms of TAAR neuron development. Understanding how different olfactory receptors couple to neural circuits mediating aversion, attraction, or other innate olfactory responses will provide basic insights into how the brain functions.

很多动物都依赖嗅觉系统以生存和繁衍，携带不同信息的气味分子或信息素被嗅觉神经元中的嗅觉受体感知后，经嗅觉环路处理进而指导动物做出正确的行为反应。脊椎动物中嗅上皮的嗅觉受体主要由两类G蛋白偶联受体组成，包括经典的气味受体（OR）和新型的痕量胺相关受体（TAAR）。痕量胺相关受体能特异识别胺类分子，并介导动物本能的行为反应。小鼠TAAR4和TAAR5分别识别天敌分泌的苯乙胺和公鼠尿液中的三甲胺，并介导截然相反的躲避和趋向行为。斑马鱼TAAR13c则识别死鱼分解物中的尸胺并介导其躲避行为。此外，人类TAAR5亦能识别三甲胺并介导躲避行为。因此，TAAR嗅觉子系统为研究动物行为编码的分子机制提供了一个非常重要的模式系统，在本项目中，我们将从发现TAAR的配体、配体结合的结构基础、嗅觉环路、TAAR受体介导的动物行物行为以及TAAR嗅觉神经元的发育机制等多个层面来解析TAAR嗅觉子系统的功能。

脊椎动物强大的嗅觉识别能力缘于多样的嗅觉受体家族成员，嗅上皮的嗅觉受体主要由两类保守的G蛋白偶联受体组成，包括经典的气味受体（OR）和新型的痕量胺相关受体（TAAR）。其中，痕量胺相关受体能特异识别胺类分子，并介导动物本能的行为反应，因此对TAAR嗅觉子系统的研究为揭示动物嗅觉行为编码的分子机制提供了一个重要的模式系统。在本项目中，我们综合利用分子生物学、细胞生物学、荧光成像、和多组学等技术手段，从发现TAAR的进化、TAAR识别的配体、配体结合TAAR的结构基础和TAAR嗅觉神经元的发育机制等多个层面解析了TAAR嗅觉子系统的功能。项目成果阐明了TAAR受体的进化起源和进化历程，解析了TAAR识别配体的结构机制及配体与受体共进化的基础，发现了TAAR嗅觉神经元亚群发育的表观调控机制，从而为理解特异嗅觉子系统的功能提供了新见解。