Transduction mechanisms and CNS targets of GC-D neurons

描述（由申请人提供）：嗅觉是了解丰富而复杂的挥发性化学物质世界的主要窗口。哺乳动物的主要和辅助嗅觉系统用于检测和分析气味和信息素。然而，越来越清楚的是，将鼻腔化学感觉神经元划分为这两组是过于简单的，并不能反映鼻子中受体细胞类型的功能多样性。在主要嗅上皮的几个区域发现了一组新的化学感觉神经元，它们针对的是一种独特的肾小球，即后嗅球中的“项链”肾小球。这些神经元也表现出不同于其他化学感觉神经元的基因表达谱。然而，目前尚不清楚这些受体神经元和肾小球是否作为一个独特的化学感觉系统起作用。我们已经创造了一种基因靶向小鼠，它在功能上破坏了编码guanyyl环化酶（GC-D）的基因，GC-D是一种对这些细胞功能至关重要的蛋白质。靶向后，该基因位点还编码一种组织化学报告蛋白，tau- β -半乳糖苷酶，使表达GC-D的神经元可视化。我们建议使用该小鼠模型对这一知之甚少的化学感觉神经元群体的组织和功能特征进行首次系统分析，并表征这些细胞在化学感觉行为中的功能作用。我们将提供这些神经元和项链肾小球的系统解剖描述，并确定GC-D在嗅觉系统中的发育和解剖表达模式。我们还将通过成年动物和新生动物的行为和生化分析来确定这些神经元的化学感觉作用。最后，我们将描述这些细胞中涉及特定化学感觉刺激（包括气味和信息素）转导的生化级联。这些研究结果将为这些神经元和肾小球检测和分析感觉刺激的机制、cGMP信号在这些过程中的作用提供重要的见解，并将定义这一独特神经元群体的感觉作用。

DESCRIPTION (provided by applicant): The sense of smell is the principal window on the rich and complex world of volatile chemicals. The main and accessory olfactory systems of mammals serve to detect and analyze odors and pheromones. However, it is becoming clear that the division of nasal chemosensory neurons into only these two groups is simplistic and does not reflect the functional diversity of receptor cell types in the nose. A novel group of chemosensory neurons, which target a unique population of glomeruli, the "necklace" glomeruli, in the posterior olfactory bulb, are found in several regions of the main olfactory epithelium. These neurons also exhibit a gene expression profile distinct from that of other chemosensory neurons. However, it is unclear if these receptor neurons and glomeruli function as a distinct chemosensory system. We have created a gene-targeted mouse that functionally disrupts the gene encoding the guanylyl cyclase, GC-D, a protein critical for the function of these cells. After targeting, this gene locus also encodes a histochemical reporter, tau-beta-galactosidase that permits the visualization of the neurons that express GC-D. We propose to use this mouse model to perform the first systematic analysis of the organization and functional characteristics of this poorly understood population of chemosensory neurons, as well as to characterize the functional role of these cells in chemosensory behavior. We will provide a systematic anatomical description of these neurons and the necklace glomeruli and determine the developmental and anatomical expression patterns of GC-D in the olfactory system. We will also determine the chemosensory role of these neurons through behavioral and biochemical analyses of adult and neonatal animals. Finally, we will characterize the biochemical cascade involved in the transduction of specific chemosensory stimuli, including both odors and pheromones, in these cells. These results obtained in these studies will provide important insights into the mechanism by which these neurons and glomeruli detect and analyze sensory stimuli, the role of cGMP signaling in these processes, and will define the sensory role of this unique neuronal population.