The Olfactory Nerve

描述（由申请人提供）：当气味配体与嗅觉感觉神经元（OSNs）纤毛上表达的分子受体结合时，嗅觉分子的感知开始于嗅觉上皮。Buck和Axel（1991）首先描述了编码气味受体的大家族基因，目前已知在小鼠中约有1200个。一个OSN只表达1个气味受体。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，嗅觉上皮是一个复杂的神经元马赛克，每个神经元只表达1200个可能的气味受体中的1个。当它们的轴突离开上皮时，它们最初与最近的邻居束状，不一定与表达相同气味受体的其他神经元的轴突束状。然而，当轴突经过嗅球表面和肾小球会聚点时，它们经历了深刻的地形重组，使得所有来自表达相同气味受体的神经元的轴突会聚到只有2/3的肾小球/嗅球。轴突的重组和汇聚到特定肾小球的过程提出了一个重要的布线问题，也许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收敛，但对束控和轴突行为的过程仍知之甚少。尽管已经有一致的努力来确定感觉轴突生长、合并和靶向的分子底物，但我们仍然对OSN轴突组织的最基本方面一无所知：轴突的初始束化是什么时候开始的，去血凝和重组的过程是什么时候？何时表达相同气味受体的同型轴突表现出不可逆粘附的证据？在嗅神经和嗅神经层的过程中，单个轴突与嗅鞘细胞的关系是什么？生长锥是如何分布和组织在束在早期发育时，当该途径建立，并在成人正在进行的轴生？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，在哪里发生？为了开始解决这些知识上的重大空白，我们提出了3个具体目标：目的1 -验证同型轴突粘附直到肾小球会聚部位近端才发生的假设；目的2：验证嗅觉感觉神经元轴突生长锥在神经束内不均匀分布的假设；目的3 -测试气味受体mrna和翻译成分在嗅觉神经/感觉轴突局部区隔的假设。

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.