Assembly of the Node of Ranvier

朗飞节点集会

• 批准号: 7363673
• 负责人: JAMES SALZER
• 金额: $ 37.03万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7363673
• 关键词: Action Potentials; Address; Ankyrins; Axon; Binding; Cell surface; Coculture Techniques; Complex; Cytoplasmic Tail; Cytoskeletal Proteins; Demyelinations; Dependence; Development; Diffuse; Disease; Epitopes; Fiber; Foundations; Image; In Situ; Label; Life; Localized; Maintenance; Mediating; NRCAM gene; Neuroglia; Nodal; Numbers; Pathogenesis; Photobleaching; Positioning Attribute; Proteins; Ranvier' s Nodes; Recruitment Activity; Role; Signal Transduction; Site; Sodium Channel; Sorting - Cell Movement; Source; Specific qualifier value; Spectrin; Surface; Transgenic Mice; Transport Vesicles; extracellular; insight; intracellular protein transport; neurofascin; nodal protein; novel; protein transport; trafficking; voltage

DESCRIPTION (provided by applicant): Action potentials are generated at the axon initial segment (AIS) and are propagated via saltatory conduction at nodes of Ranvier. These domains are highly enriched in voltage gated Na+ channels, which form a multimeric complex with beta subunits, neuronal cell adhesion molecules, notably neurofascin (NF) 186, and the cytoskeletal proteins ankyrin G and piv spectrin. We have recently demonstrated that targeting of NF186 to PNS nodes is mediated via its extracellular interactions, that it has an essential role in node formation by recruiting ankyrin G via its cytoplasmic domain, and that ankyrin G in turn, is required for the accumulation of sodium channels. In contrast, ankyrin accumulation at initial segments, which is also critical for domain organization is intrinsically specified, independent of NF186. These studies raise a number of key questions. What is the source of proteins targeted to the node and how do they traffic to this site? Are nodal components, once assembled, stably expressed at the node or do they continuously turnover and, if so, is this turnover enhanced by demyelination? Finally, do CNS nodes assemble like PNS nodes (i.e. directed by extracellular signals) or more akin to initial segments (i.e. directed from the inside-out via interactions with ankyrin G)? In this proposal, we address these questions and further characterize mechanisms of node assembly by: i) determining how proteins traffic to PNS nodes, including whether they are recruited from cell surface pools or via directed vesicular transport, ii) live image nodes to examine dynamic changes that occur during development and with demyelination, and iii) examine the dependence of CNS nodes on NF186- dependent signals in cocultures and targeting signals in transgenic mice. These studies should provide important new insights into the axo-glial interactions that regulate the assembly and maintenance of nodes of Ranvier. They will also be an important foundation for elucidating pathogenetic changes at nodes that result from demyelination.

描述（由申请人提供）：动作电位是在轴突初始段（AIS）上产生的，并通过Ranvier节点的盐传导传播。这些结构域高度富集在电压门控的Na+通道中，该通道形成了具有β亚基，神经元细胞粘附分子的多聚体配合物，尤其是神经胶质细胞（NF）186，以及细胞骨架蛋白蛋白Ankyrin g和piv Spectrin。我们最近证明，将NF186靶向PNS节点是通过其细胞外相互作用介导的，它通过通过其细胞质结构募集Ankyrin G募集Ankyrin g在节点形成中具有重要作用，而Ankyrin g又需要用于钠通道的积累。相比之下，对域组织也至关重要的初始细分处的骨蛋白积累是本质上指定的，独立于NF186。这些研究提出了许多关键问题。靶向节点的蛋白质的来源是什么？它们如何流入该网站？一旦组装而成，在节点上稳定表达还是不断营业额，如果是这样，是否通过脱髓鞘增强了这种营业额？最后，CNS节点会像PNS节点（即通过细胞外信号指示）或类似于初始段（即通过与Ankyrin g的相互作用从内而外指导）组装吗？在该提案中，我们通过以下方式解决了这些问题并进一步表征节点组装的机制：i）确定蛋白质如何流动到PNS节点，包括它们是从细胞表面池中募集还是通过有向的囊泡传输募集，ii）实时图像节点，ii）实时图像节点，以检查在开发和demyelination n. everence of Cn.nf inf inf inf inf inf inf inf inf inf。靶向转基因小鼠中的信号。这些研究应为调节Ranvier节点组装和维护的Axo-Glial相互作用提供重要的新见解。它们还将成为阐明由脱髓鞘导致的节点的致病变化的重要基础。