Molecular Characterization of Axon-Glial Interactions

轴突-神经胶质相互作用的分子表征

• 批准号: 8777105
• 负责人: MANZOOR A. BHAT
• 金额: $ 32.41万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8777105
• 关键词: Action Potentials; Applications Grants; Axon; Binding; Blood-Nerve Barrier; Complex; Cytoskeleton; Defect; Demyelinations; Development; Disease; Drosophila Nrx protein; Drosophila genus; Electrons; Elements; Embryo; Figs - dietary; Future; Genes; Health; Human; Humpback Dolphins; Immigration; Immunoglobulin Domain; Knowledge; Lead; Ligands; Light; Link; Maps; Microscopic; Molecular; Molecular Genetics; Multiple Sclerosis; Mus; Myelin; Nerve; Neuroglia; Neurons; Nodal; Orthologous Gene; Pathway interactions; Peripheral; Peripheral Nerves; Play; Potassium; Potassium Channel; Process; Proteins; Role; Septate; Set protein; Signal Pathway; Sodium; Structure; Therapeutic; Work; axonal degeneration; base; cell motility; contactin; design; fly; genetic analysis; genetic manipulation; in vivo; intermolecular interaction; migration; molecular domain; mutant; neurofascin; neuroglian; neuron development; neuropathology; neurotransmission; novel; protein expression; remyelination; scaffold

Our work demonstrates the presence of axo-glial septate junctions (AGSJs) in Drosophila nerves and establishes structural and molecular similarities between Drosophila and vertebrate AGSJs. Drosophila proteins: Neurexin IV (NRX IV), Contactin (CONT) and Neuroglian (NRG) form a tripartite complex that localizes to AGSJs. Their murine orthologs Contactin-associated protein (Caspr), Contactin (Cont) and Neurofascin (NF155) also form a complex at the paranodal AGSJs in myelinated axons. Drosophila nrx IV, cont and nrg, and mouse Caspr, Cont and NF155 mutants all fail to organize AGSJs. In addition, double mutant combinations and triple mutants of nrx IV, cont and nrg in Drosophila show severe peripheral glial migration defects and axonal degeneration in embryonic peripheral nerves, pointing to an important relationship between axon-glial interactions and axonal/glial cytoskeleton. We also discovered that in the embryonic CNS midline NRX IV functions independent of CONT and NRG, and interacts in trans with a midline glia-specific immunoglobulin (Ig) domain protein, Wrapper (WRAP). This interaction coordinates axon-glial interactions, axonal ensheathment and glial migration in the CNS midline. Together these studies lead us to hypothesize that glial migration, ensheathment, and axon degeneration are mechanistically linked. Our findings provide the basis to approach the fundamental question of how axonal ensheathment is coordinated with underlying axonal and glial cytoskeletal elements during neuron-glial interactions. Most importantly, we ask which axon-glial signaling mechanisms are essential for maintaining axonal health and neuronal functions. Identification of these mechanisms using in vivo genetic analysis will provide a basis for our attempts to identify the cellular and molecular mechanisms precipitating pathological demyelination and impeding remyelination.

我们的工作证明了轴胶质细胞分隔连接（AGSJs）的存在， 果蝇神经和建立结构和分子相似性之间 果蝇和脊椎动物AGSJS。果蝇蛋白质类：Neurexin IV（NRX IV），Contactin （CONT）和神经胶质细胞（NRG）形成定位于AGSJ的三重复合物。他们的 鼠直系同源物接触蛋白相关蛋白（Caspr）、接触蛋白（Cont）和 神经成束蛋白（NF 155）也在有髓轴突中的结旁AGSJ处形成复合物。 果蝇nrg IV、nrg和nrg以及小鼠Caspr、Cont和NF 155突变体均不能 组织AGSJS。此外，还研究了nm 23 IV的双突变体组合和三突变体， 果蝇的nrg和nrg表现出严重的周围胶质细胞迁移缺陷和轴突生长缺陷。 胚胎周围神经的退化，指出了一个重要的关系 轴突-神经胶质相互作用和轴突/神经胶质细胞骨架之间的关系。我们还发现 在胚胎CNS中线NRX IV功能独立于CONT和NRG， 与中线胶质细胞特异性免疫球蛋白（IG）结构域蛋白反式相互作用， 包装器（WRAP）。这种相互作用协调轴突-胶质细胞相互作用，轴突-胶质细胞相互作用， CNS中线的鞘化和胶质细胞迁移。这些研究共同引导我们 假设胶质细胞迁移、鞘化和轴突变性是 机械连接。我们的研究结果提供了基础，以接近基本的 问题是轴突鞘如何与下面的轴突和神经胶质细胞协调 神经元-胶质细胞相互作用过程中的细胞骨架元素。最重要的是，我们问， 轴突-神经胶质细胞信号传导机制对于维持轴突健康至关重要， 神经元功能使用体内遗传分析鉴定这些机制将 为我们试图确定细胞和分子机制提供了基础 导致病理性脱髓鞘并阻碍髓鞘再生。