Mechanisms of embryonic olfactory sensory neuron axon targeting

胚胎嗅觉感觉神经元轴突靶向机制

基本信息

批准号：
7804230
负责人：
Arie Sitthichai Mobley
金额：
$ 5.01万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7804230
关键词：
Adenylate Cyclase Affect Afferent Neurons Animals Anosmia Antibodies Axon Biochemical Biological Assay Brain Breeding Cell Communication Cell Nucleus Cells Color Complement Computer Systems Development Conflict (Psychology)Coupled Cyclic AMP Cyclic Nucleotides DNA Data Development Embryo Embryonic Development Epithelium Event Extracellular Matrix Fluorescent in Situ Hybridization GTP-Binding Proteins Gene Expression Genetic Transcription Goals Growth Cones HCN1 channel Hippocampus (Brain)Human Immunoblotting Immunohistochemistry Individual Ion Channel Kinetics Knockout Mice Knowledge Label Light Location Measurement Measures Mediating Mesenchyme Monitor Mus Neurites Neuroglia Odorant Receptors Odors Olfactory Epithelium Olfactory Pathways Pathway interactions Play Positioning Attribute Process Proteins Relative (related person)Reporting Reverse Transcriptase Polymerase Chain Reaction Rodent Role Series Signal Transduction Staging Syndrome System Testing Time Up-Regulation Wild Type Mouse adenylyl cyclase III aged axon guidance cyclic nucleotide-gated cation channel cyclic-nucleotide gated ion channels design developmental disease in vivo inhibitor/antagonist member olfactory bulb postnatal promoter protein expression protein kinase A kinase receptor research study sensory system

项目摘要

DESCRIPTION (provided by applicant): The cascade of mechanisms that regulate the outgrowth of axons from olfactory sensory neurons (OSNs) and their precise targeting to specific glomeruli in the olfactory bulb remain controversial. While the odor receptors expressed by the OSNs are strongly implicated, there are conflicting reports pertaining to the functional transduction cascade downstream from the odor receptors. An absence of functional activity induced by naris closure, or deletion of a member of the transduction cascade, adenylyl cyclase 111, can have significant effects on the organization of OSN axons and their target glomeruli. However, perturbation of the cyclic nucleotide gated (CNG) channel that is the target of cAMP within the cascade results in little perturbation of axon outgrowth/targeting. Recent findings suggested that cAMP may contribute to OSN axon outgrowth, independent of CNG channel opening, by entering the nucleus and regulating gene expression. My goal is to explore an alternative hypothesis: that 1(h), the current generated by), contributes to OSN depolarization/ excitation and in the absence of the CNG channel can underlie axon outgrowth, coalescence, and formation of glomeruli. I propose a series of studies that will establish the spatio-temporal framework of HCN subunit expression, quantify developmental transients in subunit expression, directly test the effect of HCN on axon outgrowth and branching, and finally, explore how the absence of the HCN1 subunit affects OSN convergence and targeting. The data will have significant implications for developmental disorders such as Kallman's syndrome, and more generally for understanding developmental dynamics and cell-cell interactions during the initial development of sensory systems.

描述（由申请人提供）：调节嗅觉感觉神经元（OSN）轴突生长的级联机制及其对嗅球中特定肾小球的精确靶向仍然存在争议。虽然 OSN 表达的气味受体与此密切相关，但有关气味受体下游功能转导级联的报道相互矛盾。鼻孔闭合引起的功能活性缺失，或转导级联成员腺苷酸环化酶 111 的缺失，可能对 OSN 轴突及其目标肾小球的组织产生显着影响。然而，作为级联内 cAMP 靶标的环核苷酸门控 (CNG) 通道的扰动几乎不会导致轴突生长/靶向的扰动。最近的研究结果表明，cAMP 可能通过进入细胞核并调节基因表达，促进 OSN 轴突的生长，而与 CNG 通道的开放无关。我的目标是探索另一种假设：1（h）（由）产生的电流有助于 OSN 去极化/激发，并且在 CNG 通道不存在的情况下可以成为轴突生长、聚结和肾小球形成的基础。我提出了一系列研究，将建立 HCN 亚基表达的时空框架，量化亚基表达的发育瞬态，直接测试 HCN 对轴突生长和分支的影响，最后探索 HCN1 亚基的缺失如何影响OSN 融合和目标定位。这些数据将对卡尔曼综合症等发育障碍产生重大影响，更广泛地对于理解感觉系统初始发育过程中的发育动力学和细胞间相互作用具有重要意义。