AXON GUIDANCE IN THE SPINAL CORD

轴突朝向它们的目标的引导是 选择性神经连接的发展。该计划的长期目标是 这项建议中描述的实验是为了确定细胞和 轴突和生长锥体引导不足的分子事件 向哺乳动物中枢神经系统内的目标移动。这项工作 重点介绍脊髓内连合神经元轴突的导航 绳索朝向他们轨迹中的中间目标，地板 位于脊髓腹侧中线的细胞。的投射 连合神经元是定型的，发生在两个阶段，最初 腹侧伸展受限于脊髓的侧缘， 随后的投射指向中线内侧和腹侧。 这种刻板印象的途径可能是由于存在几个不同的 引导线索。这项建议的目的是审查性质和 这些线索的作用。 初步实验表明，在这一过程中采取的途径 最初的连合轴突的腹侧延伸限于 脊髓神经上皮细胞表达细胞外基质成分， 由抗体INO识别的，可能含有层粘连蛋白-肝素 硫酸盐蛋白多糖复合体。细胞外基质在血管生成中的作用 限制连合轴突的生长将在体外进行检查。这个 将检查INO复合体上的连合轴突的延伸。在……里面 此外，针对INO的抗体调节轴突的能力 延期将另行确定。最后，受体在连合中的作用 将检查底物中糖蛋白的轴突。 我们已经证明，底板细胞释放一种趋化因子， 影响体外培养的连合轴突的生长方向 负责连合轴突向地板的内侧轨迹 活体内的平板。这提供了第一个实验证据 趋化作用与中枢神经发育的关系 系统。我们将详细研究趋化作用，重点放在 热带因素作用的时间进程和范围。此外, 将测定该因子的生化性质，以便 便于提纯和分析其作用机制。 拟议中的实验应该会增强我们对自然的理解， 导致发展的事件的调节和相互作用 一组中枢神经元、脊髓连合神经元的运动轨迹 电源线。这些信息还将使我们能够确定其中有多少 机制很可能被用于发展中的中央银行的其他部分。 神经系统。最初轴突延伸背后的许多机制 轴突投射对适当靶点的引导也可以 对于轴突的再生是必不可少的。对这些机制的理解是 对我们治疗退行性或发育性疾病的能力至关重要 神经系统的一部分。

The guidance of axons towards their targets is one of the first steps in the development of selective neural connections. The long term aim of the experiments described in this proposal is to determine the cellular and molecular events that underly the guidance of axons and growth cones towards their targets within the mammalian central nervous system. The work focuses on the navigation of the axons of commissural neurons in the spinal cord towards an intermediate target in their trajectory, the floor plate cells at the ventral midline of the spinal cord. The projection of commissural neurons is stereotyped and occurs in two stages, the initial ventral extension being confined to the lateral edge of the spinal cord and the subsequent projection directed medially and ventrally to the midline. This stereotyped pathway may be due to the presence of several distinct guidance cues. The purpose of this proposal is to examine the nature and function of these cues. Preliminary experiments have revealed that the pathway taken during the initial ventral extension of commissural axons is restricted to a region of spinal cord neuroepithelium expressing an extracellular matrix component, recognized by the antibody INO, and probably comprising a laminin-heparan sulphate proteoglycan complex. The role of the extracellular matrix in restricting the growth of commissural axons will be examined in vitro. The extension of commissural axons on the INO complex will be examined. In addition, the ability of antibodies directed against INO to modulate axonal extension will be determined. Finally, the role of receptors on commissural axons for the glycoproteins in the substratum will be examined. We have shown that floor plate cells release a chemoattractant factor that influences the direction of growth of commissural axons in vitro and may be responsiblefor the medial trajectory of commissural axons towards the floor plate in vivo. This provides the first experimental evidencefor the involvement of chemotropism in the developmentof the central nervous system. The chemotropic effect will be examined in detail with emphasis on the time course and range of the action of the tropic factor. In addition, the biochemical properties of the factor will be determined in order to facilitate its purification and the analysis of its mechanism of action. The proposed experiments should enhance our understanding of the nature, regulation and interaction of events leading to the developmental trajectory of one set of central neurons, commissural neurons of the spinal cord. The information will also permit us to determine how many of these mechanisms are likely to be used in other parts of the developing central nervous system. Many of the mechanisms underlying initial axonal extension and the guidance of axonal projections towards appropriate targets may also be essential for regeneration of axons. Understandingthese mechanisms is fundamental to our ability to treat degenerative or developmental disorders of the nervous system.