DEVELOPMENT OF NEURONAL SPECIFICITY

描述（研究者摘要）：生长锥，生长尖端 轴突，被认为是神经元的寻路器官。他们 通过直接的丝状伪足接触来感知许多引导线索，但它一直是 不清楚这种接触实际上是如何引导生长锥的。这项建议 集中在一个令人惊讶的接触介导的指导方面， 这是用延时显微镜在分离的细胞中检测到的， 文化感觉神经元的生长锥对 接触三种鸟类， 胚胎丝状伪足接触特异性地改变了 生长锥本身。1)局部接触后巩膜 抑制面纱的延伸。2)局部接触雪旺细胞 刺激大面纱的突出并增加面纱的稳定性。第三章 与前巩膜接触增加双丝状伪足突出 覆盖整个生长锥，然后局部刺激 优惠合并。这些生理相关的反应是 足以偏置行进方向并调节诸如 避免，但比粗暴的行为更稳定。使全党 似乎是与寻路最相关的组件。的 反应的特异性强有力地证明了 分子水平。在接触时，特异性配体-受体结合可能是 调节可区分的第二信使系统， 细胞骨架动力学的改变。去调查每一个 反过来，这些不变的响应将被用作测定。目的 1表征了细胞表面分子活性，这些活性对于以下两种生物活性至关重要： 通过测试试点研究中涉及的候选人的反应。目的2 评估钙和其他第二信使候选者在 三个答案中的每一个。Aim 3表征细胞骨架变化 在与每个群体接触时，将光学记录相互作用， 用或不用外源性化学物质处理，其特征在于 详细这项工作将阐明控制轴突的机制， 寻路是人类神经发育的基本过程

DESCRIPTION (Investigator's Abstract): Growth cones, the growing tips of axons, are considered the pathfinding organ of the neuron. They sense many guidance cues by direct filopodial contact, but it has been unclear how the contact actually directs growth cones. This proposal focuses on a surprisingly specific aspect of contact-mediated guidance that was detected using time-lapse microscopy in dissociated cell culture. Growth cones of sensory neurons respond specifically to contact with three populations that they normally encounter in the avian embryo. Filopodial contact specifically alters the motile activity of the growth cone itself. 1) Contact with posterior sclerotome locally inhibits extension of veils. 2) Contact with Schwann cells locally stimulates protrusion of large veils and increases veil stability. 3) Contact with anterior sclerotome increases protrusion of both filopodia and veils throughout the growth cone and then locally stimulates preferential consolidation. These physiologically relevant responses are sufficient to bias the direction of travel and to mediate behaviors such as avoidance, but are more invariant than the gross behavior. They thus appear to be the component that is most relevant to pathfinding. The specificity of the responses strongly argues for specificity at the molecular level. On contact, specific ligand-receptor binding is likely to modulate distinguishable second messenger systems that cause specific alterations in cytoskeletal dynamics. To investigate each of these elements in turn, these invariant responses will be used as assays. Aim 1 characterizes cell surface molecular activities essential for two of the responses by testing candidates implicated in pilot studies. Aim 2 assesses the role of calcium and other second messenger candidates in each of the three responses. Aim 3 characterizes cytoskeletal changes on contact with each population Interactions will be optically recorded, with or without treatments with exogenous chemicals, and characterized in detail. This work will elucidate mechanisms that control axonal pathfinding, a process fundamental to human neural development.