Molecular Mechanisms of Olfactory Receptor Choice

描述（由申请人提供）：哺乳动物嗅觉的显著敏感性和特异性来自于在分子、细胞和组织水平上建立感觉器官的贡献。嗅觉受体（OR）蛋白是这一发育过程中最重要的组成部分之一。这个大的家族相关的GPCR偶联受体主要负责定义气味的范围，可以被一个有机体检测到。观察到每个嗅觉神经元表达单一类型的OR对信息编码具有重要意义。也就是说，配体/或与单一受体类型相互作用的结果可以直接转化为生理信号，细胞传播到大脑前部的嗅球。此外，进入嗅球的轴突输入的分离，根据每个细胞表达的OR进行组织，扩展了这种关系，使得每个离散的肾小球代表一个信息单元，报告环境中是否存在挥发物。虽然这个初始信号需要嗅球和更高的大脑区域进行广泛的进一步处理，以产生与哺乳动物嗅觉相关的复杂的气味感知和识别，但在每个成熟的嗅觉神经元中选择性地表达一个OR对于该感觉系统中准确的信息流至关重要。如果缺乏这种高度调控的表达机制，嗅觉受体神经元的响应特征及其对嗅球的准确组织将受到严重影响。尽管OR基因调控至关重要，但我们对嗅觉功能中与OR选择和调控相关的事件知之甚少。在本提案中，我们将定义嗅觉受体神经元在每个成熟感觉神经元中选择性表达单一嗅觉受体蛋白类型所利用的关键步骤。这些实验将为建立功能性嗅觉系统的最关键事件之一提供新的见解，并阐明特定调节蛋白在这一过程中的作用。此外，哺乳动物嗅觉受体的调控为单等位基因表达提供了一个有价值的范例，这对于正常健康和疾病相关基因的正确表达至关重要。

DESCRIPTION (provided by applicant): The remarkable sensitivity and specificity of mammalian olfaction arises from the contributions at the molecular, cellular and tissue levels to establish a sensory organ. One of the most important components in this developmental process is the olfactory receptor (OR) protein. This large family of related GPCR coupled receptors is primarily responsible for defining the range of odorants that can be detected by an organism. The observation that each olfactory neuron expresses a single type of OR has important implications for information coding. Namely, the consequences of a ligand/OR interaction with a single receptor type can be directly translated into the physiological signal that the cell propagates to the olfactory bulb at the front of the brain. Additionally, the segregation of the axonal inputs into the olfactory bulb, organized according to the OR that each cell expresses, extends this relationship such that each discrete glomeruli represents an information unit reporting whether volatiles are present in the environment. Although extensive further processing of this initial signal by the olfactory bulb and higher brain areas is required to generate the complex perception and identification of odors associated with mammalian olfaction, the selective expression of exactly one OR in each mature olfactory neuron is critical for accurate information flow in this sensory system. In the absence of this highly regulated expression mechanism, the response profile of olfactory receptor neurons (ORNs) and the accurate organization of their projections to the olfactory bulb would be severely compromised. In spite of the critical importance of OR gene regulation, we know surprisingly little about the events associated with OR choice and regulation in olfactory function In this proposal, we will define the key steps utilized by olfactory receptor neurons to generate the selective expression of a single olfactory receptor protein type in each mature sensory neuron. These experiments will afford new insights into one of the most critical events in the establishment of a functional olfactory system and elucidate the role of specific regulatory proteins in this process. In addition, the regulation of the mammalian olfactory receptors provides a valuable paradigm for monoallelic gene expression that is critical for the proper expression of several genes that contribute to normal health and disease.