The Olfactory Nerve

描述（由申请人提供）：当气味配体与嗅觉感觉神经元（OSN）纤毛上表达的分子受体结合时，气味分子的感知开始于嗅觉上皮。Buck和阿克塞尔（1991）是第一个描述编码气味受体的基因大家族的人，现在已知小鼠中有大约1,200个。OSN仅表达1种气味受体。表达相同受体的OSN不会聚集在一起，而是广泛分布在上皮中。因此，嗅上皮是一个复杂的神经元镶嵌体，每个神经元只表达1,200种可能的气味受体中的一种。当它们的轴突离开上皮细胞时，它们最初与最近的邻居成束，而不一定与来自表达相同气味受体的其他神经元的轴突成束。然而，当它们在嗅球表面和肾小球会聚点上前进时，轴突经历深刻的地形重组，使得来自表达相同气味受体的神经元的所有轴突仅会聚到2/3肾小球/嗅球中。轴突重组和会聚成特定肾小球的过程构成了一个重要的布线问题，可能是感觉系统中最复杂的布线问题。人们普遍认为气味受体本身有助于同型轴突的会聚，但对成束和轴突行为的过程仍然知之甚少。尽管一致努力确定的感觉轴突的生长，合并和靶向的分子基板，我们仍然可悲的是无知的OSN轴突组织的最基本的方面：什么时候开始的轴突最初的fasciculation，fasciculation和重组的过程开始？表达相同气味受体的同型轴突何时表现出不可逆粘附的证据？在嗅神经和嗅神经层中，轴突与嗅鞘细胞沿着走行的关系如何？生长锥是如何分布和组织的束无论是在早期发展时的途径是建立和在成年人正在进行的轴突？气味受体mRNA在轴突中何时何地表达？mRNA的局部轴突翻译是否发生，如果发生，在什么条件下，在哪里？为了开始解决我们知识中的这些重大空白，我们提出了3个具体目标：目标1 -检验同型轴突在接近肾小球会聚部位之前不会发生粘附的假设;目标2 -检验嗅觉感觉神经元轴突的生长锥在束内不均匀分布的假设;和目的3 -测试气味受体mRNA和翻译组分在嗅觉神经/感觉轴突中局部区室化的假设。

DESCRIPTION (provided by applicant): The perception of odorous molecules begins in the olfactory epithelium when odorant ligands bind to molecular receptors expressed on the cilia of the olfactory sensory neurons (OSNs). Buck and Axel (1991) were the first to describe the large family of genes coding for the odorant receptors, now known to number ~1,200 in mice. An OSN expresses only 1 odorant receptor. OSNs expressing the same receptor do not cluster together but rather are broadly distributed across the epithelium. Thus the olfactory epitheium is a complex mosaic of neurons each of which expresses only 1 of 1,200 possible odorant receptors. As their axons exit the epithelium they initially fasciculate with nearest neighbors, no necessarily with axons from other neurons expressing the same odorant receptor. However, as they progress over the surface of the olfactory bulb and a point of glomerular convergence, the axons undergo a profound topographical reorganization such that all of the axons coming from neurons expressing the same odorant receptor converge into only 2/3 glomeruli/olfactory bulb. This process of reorganization of axons and convergence into specific glomeruli poses a significant wiring problem, perhaps the most complex wiring problem found among sensory systems. It is widely accepted that the odorant receptors themselves contribute to the convergence of homotypic axons but the process of fasciculation and axon behavior remains poorly understood. Despite a concerted effort to identify the molecular substrates of sensory axon growth, coalescence and targeting, we remain woefully ignorant of the most fundamental aspects of OSN axon organization: When does the initial fasciculation of axons begin, the processes of defasciculation and reorganization? When do homotypic axons expressing the same odorant receptor show evidence of irreversible adhesion? What is the relationship of individual axons to the olfactory ensheathing cells along the course of the olfactory nerve and olfactory nerve layer? How are growth cones distributed and organized in the fascicles both during early development when the pathway is established and in the adult during ongoing axogenesis? Where and when is the odorant receptor mRNA expressed in axons? Does local axonal translation of mRNA occur, and if so under what conditions and where? To begin addressing these significant gaps in our knowledge we are proposing 3 specific aims: Aim 1 - Test the hypothesis that adhesion of homotypic axons does not occur until they are proximal to the site of glomerular convergence; Aim 2 - Test the hypothesis that the growth cones of olfactory sensory neuron axons are not homogeneously distributed within fascicles; and Aim 3 - Test the hypotheses that odorant receptor mRNAs and the translational components are locally compartmentalized in the olfactory nerve/sensory axons.