Laminin receptors and signals in Schwann cells

雪旺细胞中的层粘连蛋白受体和信号

基本信息

批准号：
7477232
负责人：
M. Laura Feltri
金额：
$ 23.63万
依托单位：
FONDAZONE CENT/SAN RAFFAELE/DEL MONTE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7477232
关键词：
A Mouse Affect Alleles Axon Basal lamina Biochemical Birth Cell Count Cell Nucleus Cell Proliferation Cell surface Charcot-Marie-Tooth Disease Cytoplasm Cytoskeleton Defect Development Dystroglycan Fiber Fluorochrome Focal Adhesion Kinase 1 Goals Grant Individual Integrins Laminin Laminin Receptor Length Life Ligands Link Mediating Messenger RNA Microscopy Molecular Probes Morphogenesis Movement Mus Mutagenesis Mutate Mutation Myelin Nerve Nerve Regeneration Neuropathy Pathogenesis Peripheral Nerves Phenocopy Plant Roots Proteins Radial Ranvier&apos s Nodes Rate Receptor Signaling Research Personnel Role Schwann Cells Signal Pathway Signal Transduction Signaling Molecule Sodium Channel Sorting - Cell Movement Spinal Ganglia Techniques Testing Time Transgenes Transgenic Mice Travel Vesicle Video Microscopy Virus base cellular microvillus congenital muscular dystrophy dysmyelination gastrointestinal microvillus glycosylation hereditary neuropathy in vivo man millimeter mutant myelination periaxin photoactivation programs receptor research study

项目摘要

DESCRIPTION (provided by applicant): Laminins and their receptors control nearly all aspects of peripheral nerve development and myelination. Laminin mutants cause a dysmyelinating neuropathy in man (congenital muscular dystrophy, MDC1 A) and mouse (dystrophic, dy) that manifests impaired Schwann cell-axon interactions, altered myelination and nodes of Ranvier formation. A laminin receptor, dystroglycan, also interacts with periaxin, mutated in Charcot-Marie-Tooth 4F (CMT4F). In the previous grant period we used conditional mutagenesis to disrupt singly or multiply the major laminin receptors in Schwann cells of transgenic mice, and have determined that (31 integrins are crucial for Schwann cell-axon interactions during radial sorting, dystroglycan is important for organization of nodes of Ranvier, and both dystroglycan and a6-34 integrin confer myelin stability. The emerging view is that laminin receptors have both specific and overlapping functions. In addition they control both radial and longitudinal morphogenesis of myelinated fibers, and thereby organize even molecules on the axon, at a distance from the basal lamina. The overall goal of this proposal is to understand how this occurs, defining the mechanism of action of single laminins or receptors, and the signaling pathways that they activate. We will take advantage of the unique group of conditional alleles and Cre transgenes that we produced or collected, that allow us to disrupt laminin receptors and relevant signaling molecules in Schwann cells of transgenic mice. We will combine morphological and biochemical analysis in vivo with studies of mutant cultures, time-lapse microscopy and a unique technique that preserves cytoarchitecture of live teased fibers. Combining these techniques, we will probe molecular effectors of pi integrin, of dystroglycan at nodes of Ranvier, and participation of dystroglycan with periaxin in compartmentalization of the Schwann cell cytoplasm. Observation of transport of fluorescent molecules in compartments of myelinated internodes will combine "live teasing" with photoactivation and time lapse microscopy. This comprehensive approach will establish the role of the different laminins/receptors/signaling pathways in peripheral nerve, and thereby clarify the pathogenesis of MDC1A and CMT4F mutations. The information produced by these experiments will collectively form a basis for developing treatment stategies of MDC1A, CMT4F and other hereditary neuropathies, and to promote nerve regeneration and remyelination in all neuropathies.

描述（由申请人提供）：层粘连蛋白及其受体控制周围神经发育和髓鞘形成的几乎所有方面。层粘连蛋白突变体会导致人类（先天性肌营养不良症，MDC1 A）和小鼠（营养不良，dy）出现髓鞘形成障碍性神经病，表现为雪旺细胞-轴突相互作用受损、髓鞘形成和郎飞叶结节改变。层粘连蛋白受体 Dystroglycan 也与在 Charcot-Marie-Tooth 4F (CMT4F) 中突变的 periaxin 相互作用。在之前的资助期内，我们使用条件诱变来破坏转基因小鼠雪旺细胞中的主要层粘连蛋白受体，并确定（31个整合素对于径向分选期间雪旺细胞-轴突相互作用至关重要，肌营养不良聚糖对于组织Ranvier 结，肌营养不良聚糖和 a6-34 整合素都赋予髓磷脂稳定性。新出现的观点是层粘连蛋白受体具有特异性和重叠性。此外，它们控制有髓纤维的径向和纵向形态发生，从而在距基底层一定距离的轴突上组织分子。该提案的总体目标是了解这是如何发生的，定义作用机制。我们将利用我们生产或收集的一组独特的条件等位基因和 Cre 转基因，使我们能够破坏层粘连蛋白受体和相关信号分子。在转基因小鼠的雪旺细胞中。我们将把体内形态学和生化分析与突变培养物研究、延时显微镜和保留活梳理纤维细胞结构的独特技术结合起来。结合这些技术，我们将探测 pi 整合素、朗飞结处的肌营养不良聚糖的分子效应器，以及肌营养不良聚糖与 periaxin 在雪旺细胞细胞质区室化中的参与。对有髓鞘节间室中荧光分子运输的观察将把“现场戏弄”与光激活和延时显微镜结合起来。这种综合方法将确定不同层粘连蛋白/受体/信号通路在周围神经中的作用，从而阐明 MDC1A 和 CMT4F 突变的发病机制。这些实验产生的信息将共同构成制定 MDC1A、CMT4F 和其他遗传性神经病治疗策略的基础，并促进所有神经病的神经再生和髓鞘再生。