DEVELOPMENT OF NEURONAL SPECIFICITY

拟议的研究有助于解决一个主要问题 神经生物学中悬而未决的问题：如何将精确的联系 在神经元和它们的靶子之间发展？试验性和 对一个简单的脊椎动物系统的描述性研究 鸡胚胎肌肉神经的发育 表明通过个体生长的尖端进行选择性寻路 神经突起(“生长锥体”)在形成过程中起着至关重要的作用。 所需的精确和有序的连接 神经系统才能发挥作用。到目前为止，人们对此知之甚少 生长锥体导向的细胞和分子机制。这个 拟议研究的中心目标是定义实际的细胞 调节生长锥对导航反应的机制 暗示。这个实验室最近发现了三种来源的 导航提示。这些提示的作用方式将是 通过对培养和胚胎的研究而阐明的。1)蜂窝 对轴突突起施加节段性模式的机制 将由时间推移分析相互作用的定义 已识别的运动神经元与细胞已被证明是 用于分段的导航提示的来源。2)趋化性 线索将使用一种新的体内测试来表征，该测试将 阐明特定于人口的线索对儿童的发展的作用 精确的神经支配模式。3)关于细胞的假说 多种介导间充质细胞死亡的相互作用，肌肉 肢体的形成和特定的路径选择将是 通过超微结构分析和胚胎手术进行测试。 分析在特定情况下有效的细胞机制 雏鸡的神经元路径发现应该能让我们深入了解正常 以及人类神经系统的异常发育。因素 对发展复杂的相互依存的 神经肌肉系统可能最终会被操纵来治疗 神经-肌肉相互作用的缺陷是导致 人类疾病状态。最后，对流程的理解 赋予发育胚胎连接的特异性是 与理解和适当对待 人类的特定神经再生能力相对较差。

The proposed studies contribute to the resolution of a major unsolved problem in neurobiology: how do precise connections develop between neurons and their targets? Experimental and descriptive studies of a simple vertebrate system, the development of muscle innervation in the chick embryo, have shown that selective pathfinding by the growing tips of individual neurites (the "growth cones") plays an essential role in the genesis of the precise and orderly connections that are required for the nervous system to function. As yet, little is know about the cellular and molecular mechanisms of growth cone guidance. The central aim of the proposed studies is to define the actual cellular mechanisms that mediate growth cone response to navigational cues. This laboratory has recently identified three sources of navigational cues. The mode of action of these cues will be elucidated by studies in culture and in the embryo. 1) The cellular mechanisms that impose a segmental pattern on axonal outgrowth will be defined by time lapse analysis of the interactions of identified motoneurons with cells that have been shown to be the source of the navigational cues for segmentation. 2) Chemotactic cues will be characterized using a novel in vivo assay that will clarify the role of population-specific cues to the development of precise innervation patterns. 3) Hypothesis concerning cellular interactions that many mediate mesenchymal cell death, muscle formation and specific pathway selection in the limb will be tested with ultrastructural analysis and embryonic surgeries. Analysis of the cellular mechanisms that are effective in specific neuronal pathfinding in the chick should give insights into normal and abnormal development of the human nervous system. Factors important to the development of the complexly interdependent neuromuscular system may eventually be manipulated to treat deficiencies in nerve-muscle interactions that are responsible for human disease states. Finally, an understanding of the processes conferring specificity on developing embryonic connections is relevant to an understanding and proper treatment of the relatively poor specific nerve regeneration in humans.