DEVELOPMENT OF NEURONAL SPECIFICITY

拟议的研究有助于解决一个重大的 神经生物学的未解决问题： 在神经元和它们的目标之间发展？实验和 一个简单的脊椎动物系统的描述性研究， 鸡胚肌肉神经支配的发育， 显示了个体生长尖端的选择性寻路 神经突（"生长锥"）在神经元的发生中起着重要作用。 精确而有序的连接， 神经系统的功能。 到目前为止，人们对 生长锥引导的细胞和分子机制。 的 提出的研究的中心目标是确定实际的细胞 调节生长锥对导航的反应的机制 线索 该实验室最近确定了三种来源， 导航线索。 这些线索的作用模式将是 通过对培养物和胚胎的研究阐明了这一点。 1)蜂窝 对轴突生长施加节段模式的机制 将通过对以下因素相互作用的时间推移分析来定义 确定运动神经元的细胞已被证明是 用于分割的导航线索的来源。 2)趋化 线索将使用一种新的体内测定法来表征， 阐明特定人群线索对发展的作用， 精确的神经支配模式 3)关于细胞的假设 许多介导间充质细胞死亡、肌肉 形成和特定的路径选择在肢体将是 通过超微结构分析和胚胎手术进行检测。 分析细胞机制，是有效的具体 小鸡的神经元寻路应该可以让我们了解正常的 以及人类神经系统的异常发育。 因素 重要的是发展复杂的相互依存的 神经肌肉系统可能最终被操纵来治疗 神经-肌肉相互作用的缺陷， 人类疾病状态。 最后，对过程的理解 赋予发育中的胚胎连接特异性， 与理解和适当处理 相对较差的特定神经再生。

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.