Odorants, Receptors and Glomeruli

描述(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一个有吸引力的模型系统。嗅觉神经元(OSN)表达小鼠基因组中大约1000个完整的气味受体(OR)基因之一。表达某一特定OR基因的OSNs胞体分散在嗅上皮内的四个区域之一，它们的轴突汇聚在小鼠嗅球内约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，每个群体表达一个不同的OR，必须被分类到大约1800个肾小球上。是什么定义了球茎中表达给定OR或对给定气味做出反应的OSN轴突汇聚的位置？我们对定义肾小球位置的参数的了解进展缓慢。目前还没有关于肾小球排列的系统研究，而且文献是跨物种、气味、ORs和肾小球的。一种研究肾小球收敛的有效方法是靶向突变OR基因，在表达给定OR基因的OSN中表达轴突标记。这些实验表明，OR是轴突汇聚到肾小球的关键决定因素。在这里，我们提出了一种协调的、系统的方法，重点放在小鼠身上，并基于ORs和肾小球的有意义的子集。这种方法是分子生物学和遗传学、生理学和解剖学的综合结合。我们的假设是，在小鼠嗅球的肾小球阵列中定义邻居的参数是：OR序列特征、气味反应以及OR表达的开始和区域。具体目标1：如何根据气味受体序列和气味响应性来定义邻近的肾小球？具体目标2：在一个已知的基因组位置上，两个相关OR基因家族的肾小球组织是什么？具体目标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?