Matrix Control of Glial/Axonal Interactions in Developing Nerves

神经发育中神经胶质/轴突相互作用的基质控制

• 批准号: 7571086
• 负责人: BRUCE L PATTON
• 金额: $ 20.21万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-16 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571086
• 关键词: Address; Affect; Axon; Basal lamina; Brain; Caliber; Cell Count; Cell Proliferation; Complement; Complex; Cues; Data; Defect; Demyelinating Diseases; Development; Dystroglycan; Embryo; Extracellular Matrix; Generations; Glycoproteins; Growth; Individual; Integrins; Investigation; Laminin; Laminin Receptor; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Methods; Mitotic; Mus; Mutant Strains Mice; Mutation; Nerve; Neuroglia; Neurons; Neurophysiology - biologic function; Numbers; Outcome; Pathway interactions; Peripheral Nerves; Peripheral Nervous System; Phenotype; Population; Process; Proliferating; Protein Isoforms; Proteins; Public Health; Publishing; Rate; Recovery; Role; Schwann Cells; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Specificity; Surface; Testing; Transgenes; base; cell growth; density; improved; laminin-8; loss of function mutation; mutant; myelination; nerve injury; nervous system disorder; receptor; recombinase; relating to nervous system; size; therapeutic target; tumorigenesis

DESCRIPTION (provided by applicant): Project Summary In the normal brain, glial cells grow and differentiate under strict controls that match the mature glial population to the local population of neuronal partners. Defects in the mechanisms controlling glial cell growth contribute to oncogenesis in the brain and peripheral nervous system. Conversely, insufficient glial cell numbers are associated with functional deficits in multiple neurological diseases. However, signals coordinating glial cell growth and differentiation are not understood. Here, we address cues that coordinate the proliferation and pro- myelinating differentiation of Schwann cells. Schwann cells in myelinated peripheral nerves establish 1:1 relationships with axons. We found peripheral nerves in mice lacking a pair of matrix proteins, laminins-2 and - 8, are fully "amyelinated". Specifically, Schwann cells lacking these proteins on their surfaces fail to proliferate to match the number of axons, and fail to isolate and myelinate individual axons. Laminins-2 and -8 are the principal glycoproteins in the Schwann cell basal lamina. Contrary to previous assumptions, however, we found they do not act by promoting basal lamina formation. Rather, laminin-2 and -8 each contributes a critical signaling activity, which together promote Schwann cell proliferation and pro-myelinating differentiation. Based on further evidence, we hypothesize laminin-2 and laminin-8 differentially regulate proliferation and differentiation through separate receptor pathways. This project will test this hypothesis by combining loss-of- function mutations in primary laminin receptors with loss-of-function mutations in laminin-2 and laminin-8. We predict distinct defects in the ability of Schwann cells to proliferate and/or differentiate predicted for specific mutant combinations. Quantitative and immunochemical methods will be used to characterize Schwann cell development. By identifying signaling pathways that choreograph neuron:glia interactions in developing nerves, the results will guide the development of therapeutic targets to improve recovery following nerve injury, slow the progression of neurological diseases, and arrest neural cancers. PUBLIC HEALTH RELEVANCE: The number of glial cells in myelinated nerves precisely matches the size and number of neuronal processes. Defects in controlling glial cell growth and differentiation cause brain cancers, and inhibit recovery of neural function following neural injuries and demyelinating diseases. However, the mechanisms controlling glial cells in normal development are not understood. This project will study how the growth of peripheral nerve glial cells, called Schwann cells, is regulated by dominant signaling components concentrated in the extracellular matrix of the developing nerve.

描述（由申请人提供）：项目概述在正常大脑中，神经胶质细胞在严格控制下生长和分化，使成熟的神经胶质细胞群与神经元伴侣的局部群体相匹配。控制神经胶质细胞生长的机制缺陷有助于脑和外周神经系统中的肿瘤发生。相反，胶质细胞数量不足与多种神经系统疾病的功能缺陷有关。然而，协调神经胶质细胞生长和分化的信号尚不清楚。在这里，我们讨论了协调许旺细胞增殖和髓鞘前分化的线索。有髓周围神经中的雪旺细胞与轴突建立1：1的关系。我们发现，缺乏一对基质蛋白（层粘连蛋白-2和层粘连蛋白-8）的小鼠外周神经完全“无髓鞘化”。具体来说，表面缺乏这些蛋白质的雪旺细胞无法增殖以匹配轴突的数量，并且无法分离和髓鞘化单个轴突。层粘连蛋白-2和层粘连蛋白-8是雪旺细胞基底层中的主要糖蛋白。然而，与以前的假设相反，我们发现它们并不通过促进基底层形成来起作用。相反，层粘连蛋白-2和层粘连蛋白-8各自贡献关键的信号传导活性，其一起促进许旺细胞增殖和前髓鞘化分化。基于进一步的证据，我们假设层粘连蛋白2和层粘连蛋白8通过不同的受体途径差异调节增殖和分化。该项目将通过将初级层粘连蛋白受体的功能丧失突变与层粘连蛋白-2和层粘连蛋白-8的功能丧失突变相结合来测试这一假设。我们预测特定突变组合预测的许旺细胞增殖和/或分化能力存在明显缺陷。将使用定量和免疫化学方法表征雪旺细胞发育。通过识别在发育神经中编排神经元：胶质细胞相互作用的信号通路，结果将指导治疗靶点的开发，以改善神经损伤后的恢复，减缓神经系统疾病的进展，并阻止神经癌症。公共卫生相关性：有髓鞘神经中神经胶质细胞的数量与神经元突起的大小和数量精确匹配。控制神经胶质细胞生长和分化的缺陷会导致脑癌，并抑制神经损伤和脱髓鞘疾病后神经功能的恢复。然而，在正常发育中控制神经胶质细胞的机制尚不清楚。该项目将研究周围神经胶质细胞（称为Schwann细胞）的生长如何受到集中在发育神经细胞外基质中的主导信号成分的调节。