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：
8533694
负责人：
MANZOOR A. BHAT
金额：
$ 16.65万
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/8533694
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.

我们的工作证明了在果蝇神经并在果蝇和脊椎动物AGSJS。果蝇蛋白：Neurexin IV（NRX IV），接触蛋白（续）和Neuroglian（NRG）形成了将AGSJS定位的三方复合物。他们的鼠直系同源物接触蛋白相关蛋白（CASPR），contactin（续）和 Neurofascin（NF155）在髓鞘轴突中的偏anodalAgsjs中也形成一个复合物。果蝇NRX IV，续和NRG以及小鼠CASPR，cont和NF155突变体都无法组织AGSJS。另外，NRX IV的双突变体组合和三重突变体，果蝇中的cont和nrg显示出严重的外围神经胶质迁移缺陷和轴突胚胎外周神经的变性，指出重要关系在轴突 - 胶质相互作用和轴突/神经胶质细胞骨架之间。我们还发现在胚胎中心中线中线NRX IV功能中，独立于con和nrg，以及与中线胶质特异性免疫球蛋白（Ig）结构蛋白相互作用，包装器（包装）。这种相互作用会协调轴突 - 轴相互作用，轴突中枢神经系统中线的迁移和神经胶质迁移。这些研究共同使我们进入假设神经胶质迁移，套装和轴突变性是机械链接。我们的发现提供了基本的基础轴突宿内如何与基础轴突和神经胶质协调的问题神经元相互作用期间的细胞骨架元素。最重要的是，我们问哪个轴突胶质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识别细胞和分子机制提供了基础促进病理脱髓鞘和阻碍再生。