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（称为雪旺细胞）生长和分化的细胞和分子机制。正常情况下，雪旺细胞增殖并形成特异性分化表型与神经轴突的数量和亚型成正比，并与之相关。雪旺细胞生长和分化缺陷是先天性和获得性神经系统疾病的原因，并限制了创伤和/或手术后运动和感觉神经的再生能力。本项目研究了在“径向轴突分选”发育过程中，未成熟的雪旺细胞增殖、分化并与轴突建立成熟的髓鞘或非髓鞘关系时，协调雪旺细胞增殖和前髓鞘分化的信号通路。我们已经确定了雪旺细胞基层的两种成分，即层蛋白-211和-411，它们是雪旺细胞开始轴突分选所必需的。它们具有非冗余的活动，暗示着独立的信号轴。为了验证这一假设，我们将层粘连蛋白2和层粘连蛋白8初级受体的功能丧失突变与层粘连蛋白2和层粘连蛋白8的功能丧失突变结合起来。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组合，从而建立假定的信号轴的身份。定量和免疫化学方法将用于表征雪旺细胞在突变组合中的发育。通过确定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。

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.