Matrix Control of Glial/Axonal Interactions in Developing Nerves

在正常的大脑中，神经胶质细胞在严格的控制下生长和分化，使成熟的神经胶质细胞群体与当地的神经伴侣群体相匹配。控制神经胶质细胞生长的机制缺陷导致大脑和周围神经系统的肿瘤发生。相反，神经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，我们解决的线索，协调增殖和前髓鞘分化的雪旺细胞。髓鞘周围神经中的雪旺细胞与轴突呈1:1关系。我们发现，缺乏一对基质蛋白（层粘连蛋白-2和- 8）的小鼠周围神经是完全“髓鞘化”的。具体来说，表面缺乏这些蛋白的雪旺细胞不能增殖以匹配轴突的数量，也不能分离单个轴突并形成髓鞘。层粘连蛋白-2和-8是雪旺细胞基底层的主要糖蛋白。然而，与先前的假设相反，我们发现它们并不通过促进基底层的形成而起作用。相反，层粘连蛋白-2和-8各自参与关键的信号活动，共同促进雪旺细胞增殖和促髓鞘分化。基于进一步的证据，我们假设laminin-2和laminin-8通过不同的受体途径调节增殖和分化。本项目将通过结合初级层粘连蛋白受体的功能丧失突变和层粘连蛋白-2和层粘连蛋白-8的功能丧失突变来验证这一假设。我们预测了雪旺细胞增殖和/或分化能力的明显缺陷，预测了特定突变组合。定量和免疫化学方法将用于表征雪旺细胞的发育。通过识别神经发育过程中神经元与神经胶质相互作用的信号通路，该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：髓鞘神经中胶质细胞的数量与神经元突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，控制神经胶质细胞正常发育的机制尚不清楚。该项目将研究周围神经胶质细胞（称为雪旺细胞）的生长如何受到集中在发育中的神经细胞外基质中的主要信号成分的调节。

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.