Molecular Characterization of Axon-Glial Interactions

轴突-神经胶质相互作用的分子表征

基本信息

批准号：
8411122
负责人：
MANZOOR A. BHAT
金额：
$ 31.27万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8411122
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 Signal Transduction 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 novel protein expression remyelination scaffold

项目摘要

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隔膜连接（AGSJ）的存在果蝇神经并建立了结构和分子之间的相似性果蝇和脊椎动物 AGSJ。果蝇蛋白：Neurexin IV (NRX IV)、Contactin (CONT) 和 Neuroglian (NRG) 形成定位于 AGSJ 的三方复合体。他们的鼠类直系同源物 Contactin 相关蛋白 (Caspr)、Contactin (Cont) 和神经成束蛋白 (NF155) 也在有髓轴突的节旁 AGSJ 处形成复合物。果蝇 nrx IV、cont 和 nrg，以及小鼠 Caspr、Cont 和 NF155 突变体均未能组织 AGSJ。此外，nrx IV的双突变体组合和三突变体，果蝇中的 cont 和 nrg 显示严重的外周胶质细胞迁移缺陷和轴突胚胎周围神经的退化，表明了重要的关系轴突-神经胶质相互作用和轴突/神经胶质细胞骨架之间。我们还发现在胚胎 CNS 中线中，NRX IV 功能独立于 CONT 和 NRG，并且与中线神经胶质细胞特异性免疫球蛋白（Ig）结构域蛋白反式相互作用，包装纸（WRAP）。这种相互作用协调轴突-神经胶质相互作用，轴突中枢神经系统中线的鞘和神经胶质细胞迁移。这些研究共同引导我们假设神经胶质细胞迁移、鞘化和轴突变性是机械地联系在一起。我们的研究结果为接近基本原理提供了基础轴突鞘如何与底层轴突和神经胶质协调的问题神经元-胶质细胞相互作用期间的细胞骨架元件。最重要的是，我们问哪个轴突-神经胶质信号传导机制对于维持轴突健康和神经元功能。使用体内遗传分析鉴定这些机制将为我们尝试识别细胞和分子机制提供基础促进病理性脱髓鞘并阻碍髓鞘再生。