CONTROL OF SCHWANN CELL DIFFERENTIATION

细胞外基质影响细胞生长的机制 人们对增殖或分化的决定知之甚少。期间 在过去的十年中，许多细胞外基质结合蛋白被 他们现在被描述为一个大家庭的成员， 整合素受体II IL，越来越认识到整合素不 不仅与基质成分结合，而且与细胞骨架相互作用， 并启动信号传导途径， 细胞增殖和分化。施万细胞（SC）， 周围神经系统的髓鞘形成细胞，是 这种细胞完全依赖于细胞外 矩阵，以区分在响应轴突信号表达 by neurons神经元.虽然这一观察是在近15年前作出的，但我们 现在才准备好描绘这背后的分子机制， 细胞外基质沉积和SC的相互依赖性 分化该提案提供了实验策略， 允许确定以下内容：1）是否α 6 β 1和 已知由SC表达的α 6 β 4整合素在SC中起作用， 分化成髓鞘形成细胞，2）无论是β 1还是β 4 整合素活化，或肌动蛋白为基础的细胞骨架，与 髓鞘特异性蛋白或其mRNA的表达，3）β 1 或β 4整联蛋白与肌动蛋白、肌动蛋白结合蛋白相互作用， 信号分子如新描述的粘着斑激酶， 以形成稳定的跨膜复合物，该复合物在SC结合至 细胞外基质，和4）酪氨酸磷酸化事件是否 与整联蛋白介导的信号转导相关并为整联蛋白介导的信号转导所必需。 这些研究将在SC与感觉神经元的共培养物中进行。 神经元允许1）精确控制SC增殖， 分化，2）单分子表达的扰动 假设在SC分化中起关键作用，和3）， 可以使用细胞、分子、生物化学和 形态学技术这些研究提供的信息是 对我们理解正常细胞的控制机制至关重要 发展，并将直接适用于努力控制 例如神经纤维瘤病的肿瘤发生，以及 制定治疗策略，以减轻由以下原因引起的脱髓鞘 神经系统损伤或免疫系统攻击神经系统 机制等

The mechanisms by which the extracellular matrix influences a cell's decision to proliferate or differentiate are poorly understood. During the last decade, many extracellular matrix-binding proteins were described and they are now known to be members of a large family of integrin receptor II IL it is becoming appreciated that integrins not only bind to matrix components but also interact with.the cytoskeleton and initiate signal transduction pathways that may be critical for cellular proliferation and differentiation. The Schwann cell (SC), the myelin forming cell of the peripheral nervous system, is an example of a cell that is absolutely dependent on the deposition of extracellular matrix in order to differentiate in response to axonal signals expressed by neurons. Although this observation was made nearly 15 years ago, we are only now ready to delineate the molecular mechanisms underlying this interdependence of extracellular matrix deposition and SC differentiation. This proposal provides experimental strategies that will allow ascertainment of the following: 1) whether the alpha6beta1 and alpha 6 Beta4 integrins, known to be expressed by SCs, play a role in SC differentiation into myelin-forming cells, 2) whether Beta1 or Beta4 integrin activation, or the actin-based cytoskeleton, are associated with expression of myelin-specific proteins or their mRNAs, 3) whether Beta1 or Beta4 integrins interact with actin, actin binding proteins, and signaling molecules such as the newly-described focal adhesion kinase, to form a stable transmembrane complex that forms upon SC binding to the extracellular matrix, and 4) whether tyrosine phosphorylation events are associated with and necessary for integrin-mediated signal transduction. These studies will be conducted in co-cultures of SCs with sensory neurons that allow 1) precise control of SC proliferation and differentiation, 2) perturbation of the expression of single molecules hypothesized to play critical roles in SC differentiation, and 3) that are amenable to analysis using cellular, molecular, biochemical, and morphological techniques. The information provided by these studies is crucial to our understanding of the mechanisms controlling normal cell development and will be directly applicable to efforts to control tumorigenesis in diseases such as neurofibromatosis, as well as to develop therapeutic strategies to alleviate demyelination caused by injury to the nervous system or by attack on the nervous system by immune mechanisms.