CONTROL OF SCHWANN CELL DIFFERENTIATION

细胞外基质影响细胞生长的机制 人们对增殖或差异化的决定知之甚少。在.期间 在过去的十年中，许多细胞外基质结合蛋白 被描述，现在已知它们是一个大家族的成员 整合素受体II IL正逐渐认识到整合素不是 不仅与基质成分结合，还与细胞骨架相互作用 并启动信号转导通路，这可能是 细胞的增殖和分化。雪旺细胞(SC)， 周围神经系统的髓鞘形成细胞，是 一种完全依赖于细胞外沉积的细胞 为了响应轴突信号的表达而进行分化 由神经元控制。尽管这一观察是近15年前提出的，但我们 直到现在才准备好描述其背后的分子机制 细胞外基质沉积与SC的相互依赖 差异化。这项提议提供了试验性的战略，将 允许确定以下各项：1)字母6β1和 已知由干细胞表达的α6β4整合素在SC中发挥作用 分化为髓鞘形成细胞，2)β1或β4 整合素激活，或基于肌动蛋白的细胞骨架，与 髓鞘特异性蛋白或其mRNAs的表达，3)是否为Beta1 或Beta4整合素与肌动蛋白、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体，该复合体在SC与 细胞外基质以及4)酪氨酸磷酸化事件是否 与整合素介导的信号转导有关，也是必要的。 这些研究将在干细胞与感官细胞的共培养中进行。 允许1)精确控制干细胞增殖和 分化，2)单分子表达的微扰 假设在供应链差异化中发挥关键作用，以及3) 可以使用细胞、分子、生化和 形态技术。这些研究提供的资料如下 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 神经纤维瘤病等疾病的肿瘤发生，以及 制定治疗策略以缓解由以下原因引起的脱髓鞘 神经系统的损伤或免疫对神经系统的攻击 机械装置。

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.