Laminin receptors and signals in Schwann cells

雪旺细胞中的层粘连蛋白受体和信号

• 批准号: 6597467
• 负责人: M. Laura Feltri
• 金额: $ 23.09万
• 依托单位: ISTITUTO SCIENTIFICO SAN RAFFAELE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6597467
• 关键词: Schwann cells; axon; biological signal transduction; clinical research; cytoskeleton; gene mutation; genetically modified animals; immunocytochemistry; integrins; laboratory mouse; laminin; myelination; neuromuscular junction; node of Ranvier; proteomics; receptor; video microscopy

DESCRIPTION (provided by applicant): Laminin is important for peripheral nerve development and myelination. Laminin mutants cause a dysmyelinating neuropathy in man (congenital muscular dystrophy, CMD) and mouse (dystrophic, dy) that manifests both impaired Schwann cell-axon interactions and altered myelination. The molecules that transduce laminin effects in Schwann cells, and the pathomechanisms of laminin mutants remain largely unknown. We have identified several laminin receptors in myelin-forming Schwann cells and shown that they are differentially expressed across peripheral nerve development, suggesting that they subserve differential roles. Our preliminary genetic analysis confirms this notion: Beta1integrin is required for establishing proper Schwann cell-axon relationships prior to birth, whereas dystroglycan is necessary for normal myelination after birth. The Beta1and dystroglycan-null morphological phenotypes suggest that these receptors normally link laminin to cytoskeletal rearrangements in Schwann cells. The overall goal of this proposal is to expand what is known of the molecular basis of laminin-cytoskeletal linkage in Schwann cells. We have produced or collected an unique group of conditional alleles and Cre transgenes that will allow us to disrupt singly or multiply all known major laminin receptors in Schwann cells of transgenic mice. Furthermore, imaging and biochemical analysis of Beta1integrin-null Schwann cells will elucidate how Beta1 directs cytoskeletal rearrangements. Proteomic analysis of Beta1integrin-null Schwann cell/neuron explants will identify candidate signal molecules that link laminin to the cytoskeletal alterations required for axonal interactions. This comprehensive approach will establish the role of the different laminin receptors in peripheral nerve, thereby clarifying the pathogenesis of CMD and dy mutations. The information produced by these experiments will collectively form a basis for developing treatment strategies of CMD and other hereditary neuropathies, and to promote nerve regeneration and remyelination in all neuropathies.

描述（由申请人提供）：层粘连蛋白对于周围神经发育和髓鞘形成很重要。层粘连蛋白突变体会导致人类（先天性肌营养不良症，CMD）和小鼠（营养不良，dy）的髓鞘形成障碍性神经病，表现为雪旺细胞-轴突相互作用受损和髓鞘形成改变。在雪旺细胞中转导层粘连蛋白效应的分子以及层粘连蛋白突变体的病理机制仍然很大程度上未知。我们在形成髓磷脂的雪旺细胞中鉴定出了几种层粘连蛋白受体，并表明它们在周围神经发育过程中表达差异，表明它们发挥着不同的作用。我们的初步遗传分析证实了这一观点：β1整合素是在出生前建立适当的雪旺细胞-轴突关系所必需的，而肌营养不良聚糖是出生后正常髓鞘形成所必需的。 Beta1 和肌营养不良聚糖无效的形态表型表明这些受体通常将层粘连蛋白与雪旺细胞中的细胞骨架重排联系起来。该提案的总体目标是扩展雪旺细胞中层粘连蛋白-细胞骨架连接的分子基础。 我们已经产生或收集了一组独特的条件等位基因和 Cre 转基因，这将使我们能够单独破坏或增殖转基因小鼠雪旺细胞中所有已知的主要层粘连蛋白受体。 此外，Beta1整合素无效的雪旺细胞的成像和生化分析将阐明Beta1如何指导细胞骨架重排。对 Beta1 整合素缺失的雪旺细胞/神经元外植体进行蛋白质组学分析，将鉴定出将层粘连蛋白与轴突相互作用所需的细胞骨架改变联系起来的候选信号分子。这种综合方法将确定不同层粘连蛋白受体在周围神经中的作用，从而阐明 CMD 和 dy 突变的发病机制。这些实验产生的信息将共同构成制定 CMD 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。