Molecular Characterization of Axon-Glial Interactions

我们的工作证明了在脑内存在轴突-神经胶质间隔连接(AGSJ)。 果蝇的神经，并在结构和分子上建立了 果蝇和脊椎动物AGSJ。果蝇蛋白：Neuresin IV(NRX IV)、Contactin (CONT)和神经胶质蛋白(NRG)形成一个定位于AGSJ的三部分复合体。他们的 小鼠触角蛋白相关蛋白(CASPR)、触角蛋白(Cont)和 神经束素(NF155)也在有髓轴突的结旁AGSJ处形成复合体。 果蝇NRX IV、CONT和NRG以及小鼠CASPR、CONT和NF155突变体均未检测到 组织AGSJ。此外，NRX IV的双突变组合和三突变组合， 果蝇CONT和NRG显示严重的外周胶质细胞迁移缺陷和轴突 胚胎周围神经的变性，表明一个重要的关系 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的功能不依赖于CONT和NRG，并且 反式与中线胶质细胞特异性免疫球蛋白(Ig)结构域蛋白相互作用， 包装器(WRAP)。这种相互作用协调轴突-神经胶质相互作用，轴突 中枢神经中线的包膜和神经胶质细胞迁移。这些研究一起将我们引向 假设神经胶质细胞迁移、包膜和轴突变性 机械连接在一起。我们的发现提供了探讨根本问题的基础 轴突被膜如何与潜在的轴突和神经胶质相协调的问题 神经元-神经胶质细胞相互作用过程中的细胞骨架元素。最重要的是，我们问哪一个 轴突-神经胶质信号转导机制对于维持轴突健康和 神经功能。使用体内遗传分析来识别这些机制将 为我们试图确定细胞和分子机制提供了基础 加速病理性脱髓鞘，阻碍再髓鞘形成。

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.