Laminin mechanisms controlling axonal sorting

描述（由申请人提供）：我们的长期目标是了解控制周围神经胶质细胞（称为许旺细胞）生长和分化的细胞和分子机制。雪旺细胞通常增殖并采用与神经中轴突的数量和亚型成正比并与其相关的特异性分化表型。雪旺细胞生长和分化的缺陷是先天性和获得性神经障碍的原因，并且限制了创伤和/或手术后运动和感觉神经的再生能力。该项目表征了在“径向轴突分选”的发育过程中协调许旺细胞增殖和前髓鞘化分化的信号通路，当未成熟的许旺细胞扩增、分化并与轴突建立成熟的髓鞘化或非髓鞘化关系时。我们已经确定了两个组成部分的雪旺细胞基底层，层粘连蛋白-211和411，这是所需的雪旺细胞开始轴突排序。它们具有非冗余的活动，涉及单独的信号轴。通过将主要层粘连蛋白受体中的功能丧失突变与层粘连蛋白-2和层粘连蛋白-8中的功能丧失突变相结合来检验这一假设。我们预测雪旺细胞增殖和/或分化能力的明显缺陷将导致特定的突变体组合，从而确定推定的信号传导轴的身份。将使用定量和免疫化学方法表征突变体组合中的雪旺细胞发育。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：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。开发有效治疗这些衰弱性疾病的主要障碍是控制神经胶质细胞发育的机制尚未得到很好的理解。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。

DESCRIPTION (provided by applicant): Our long term goal is to understand the cell and molecular mechanisms that control the growth and differentiation of peripheral nerve glial cells, called Schwann cells. Schwann cells normally proliferate and adopt specific differentiated phenotypes in direct proportion to, and association with, the number and subtype of axons in the nerve. Defects in Schwann cell growth and differentiation are the cause of congenital and acquired neurological disorders, and limit the regenerative capacity of motor and sensory nerves following trauma and/or surgery. This project characterizes signaling pathways that coordinate the proliferation and pro- myelinating differentiation of Schwann cells during the developmental process of "radial axonal sorting", when immature Schwann cells expand, differentiate, and establish mature myelinating or nonmyelinating relationships with axons. We have identified two components of the Schwann cell basal lamina, laminins-211 and -411, which are required for Schwann cells to begin axonal sorting. They have nonredundant activities, implicating separate signaling axes. To 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 will result in specific mutant combinations, thereby establishing the identity of the putative signaling axes. Quantitative and immunochemical methods will be used to characterize Schwann cell development across the mutant combinations. By identifying the 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: Defects in controlling glial cell growth and differentiation cause brain cancers, and inhibit recovery of neural function following neural injuries and demyelinating diseases. A major impediment to developing effective treatment for these debilitating conditions is that mechanisms controlling glial cell development are not well 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.