Odorants, Receptors and Glomeruli

描述（由申请人提供）：哺乳动物嗅觉系统越来越被认为是研究发育过程中神经回路形成的有吸引力的模型系统。嗅觉感觉神经元（OSN）表达小鼠基因组中约1000个完整气味受体（OR）基因中的一个。表达给定OR基因的OSN的细胞体分散在嗅上皮内的四个区域中的一个中，并且它们的轴突会聚到小鼠嗅球中约1800个肾小球中的几个上。因此，提出了一个映射问题：1000个OSN群体，每个表达不同的OR，必须分选到大约1800个肾小球。是什么定义了表达特定OR或对特定气味反应的OSN轴突在灯泡中的聚集点？我们对肾小球位置参数的理解进展缓慢。尚未对肾小球阵列进行系统研究，文献在种属、气味剂、OR和肾小球之间支离破碎。研究肾小球会聚的一种有效方法是对OR基因进行靶向诱变，以在表达给定OR基因的OSN中表达轴突标记物。这些实验表明，OR是轴突会聚到肾小球的关键决定因素。在这里，我们提出了一个协调的，系统的方法，重点放在小鼠和有意义的子集的OR和肾小球的基础上。该方法是分子生物学与遗传学、生理学和解剖学的综合结合。我们的假设是，参数定义的肾小球阵列中的小鼠嗅球的邻居是：OR序列功能，气味反应和发病和OR表达区。具体目标1：如何定义相邻肾小球的气味受体序列和气味反应性？具体目标2：什么是肾小球组织的两个家庭的相关OR基因在一个已知的基因组位点？特定目的3：OR表达的时间和区域与肾小球位置有何关系？

DESCRIPTION (provided by applicant): The mammalian olfactory system is increasingly recognized as an attractive model system for studying the formation of neural circuits during development. An olfactory sensory neuron (OSN) expresses one the of approximately 1000 intact odorant receptor (OR) genes in the mouse genome. Cell bodies of OSNs expressing a given OR gene are dispersed in one of four zones within the olfactory epithelium, and their axons converge onto a few of the approximately 1800 glomeruli in the olfactory bulb of the mouse. A mapping problem is thus posed: 1000 populations of OSNs, each expressing a distinct OR, must be sorted onto approximately 1800 glomeruli. What defines the site in the bulb to which axons of OSNs expressing a given OR or responding to given odorants converge? Progress in our understanding of the parameters defining glomerular position has been slow. No systematic studies of the glomerular array have been undertaken, and the literature is fragmented across species, odorants, ORs and glomeruli. A productive approach to study glomerular convergence has been targeted mutagenesis of OR genes to express axonal markers in OSNs expressing a given OR gene. Such experiments have revealed that the OR is a critical determinant of axonal convergence to glomeruli. Here we propose a coordinated, systematic approach focusing on the mouse and based on meaningful subsets of ORs and glomeruli. The approach is an integrated combination of molecular biology and genetics, physiology, and anatomy. Our hypothesis is that parameters defining a neighborhood in the glomerular array of the mouse olfactory bulb are: OR sequence features, odorant responsiveness and onset and zone of OR expression. Specific Aim 1: How are neighboring glomeruli defined in terms of odorant receptor sequence and odorant responsiveness? Specific Aim 2: What is the glomerular organization of two families of related OR genes at a known genomic locus? Specific Aim 3: How are time and zone of OR expression related to glomerular position?