The Olfactory Nerve

描述(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，气味分子的感知始于嗅觉上皮。Buck和Axel(1991)首先描述了气味受体的编码基因大家族，现在已知在老鼠身上有大约1,200个。OSN只表达一种气味受体。表达相同受体的OSN不是聚集在一起，而是广泛分布在上皮细胞中。因此，嗅觉上皮层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一个。当它们的轴突离开上皮时，它们最初与最近的邻居形成束状，不一定与来自其他神经元的轴突表达相同的气味感受器。然而，当它们越过嗅球表面和肾小球会聚点时，轴突经历了深刻的地形重组，以至于所有来自表达相同气味感受器的神经元的轴突都汇聚成2/3的肾小球/嗅球。轴突的重组和汇聚成特定的肾小球的过程造成了一个重大的连接问题，可能是感觉系统中发现的最复杂的连接问题。人们普遍认为气味受体本身有助于同型轴突的汇聚，但对神经束和轴突行为的过程仍知之甚少。尽管人们一致努力确定感觉轴突生长、融合和靶向的分子底物，但遗憾的是，我们仍然对OSN轴突组织的最基本方面一无所知：轴突的最初分束是什么时候开始的，脱散和重组的过程？表达相同气味受体的同型轴突何时显示出不可逆转的粘连？在嗅神经和嗅神经层的走行过程中，单个轴突与嗅鞘细胞之间有什么关系？无论是在早期发育的过程中，还是在正在进行的轴突发生过程中，生长锥在神经束中是如何分布和组织的？气味受体mRNA在轴突中何时何地表达？MRNA的局部轴突翻译发生了吗？如果发生了，在什么条件下和在哪里发生？为了开始解决我们知识中的这些显著差距，我们提出了三个具体目标：目标1-测试同型轴突直到它们靠近肾小球会聚部位才会发生粘连的假设；目标2-测试嗅觉神经元轴突的生长锥体不均匀分布在神经束内的假设；以及目标3-测试气味受体mRNAs和翻译成分在嗅神经/感觉轴突中局部分隔的假设。

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.