Semaphorin-Mediated Neuronal Growth Cone-Guidance

信号蛋白介导的神经元生长锥引导

• 批准号: 8550178
• 负责人: ALEX L KOLODKIN
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550178
• 关键词: Address; Affect; Amacrine Cells; Axon; Biological Assay; Brain; Cell Nucleus; Cells; Code; Complex; Cues; Dendrites; Diagnostic; Disease; Drosophila genus; Event; Funding; Generations; Genes; Genetic; Goals; Growth Cones; In Vitro; Inner Plexiform Layer; Interneurons; Lead; Ligands; Medial; Mediating; Midbrain structure; Molecular; Molecular Genetics; Morphology; Mus; Nervous system structure; Neurons; Optics; Pattern; Phylogenetic Analysis; Play; Process; Receptor Signaling; Regulation; Retina; Retinal; Retinal Ganglion Cells; Role; Semaphorins; Sensory; Signal Transduction; Structure; Synapses; System; Therapeutic; Work; base; fly; in vivo; insight; neural circuit; neurodevelopment; neuronal growth; neuronal guidance; neuropsychiatry; novel; outer plexiform layer; plexin; receptor; relating to nervous system; response; retinal neuron; synaptogenesis

DESCRIPTION (provided by applicant): The generation of neural connectivity critically depends upon temporally and spatially coordinated regulation of neuronal process guidance. The central goal of this proposal is to understand the functions and mechanisms employed by specific neuronal semaphorin guidance cues to regulate axonal and dendritic targeting. A range of cues and their receptors play key roles in attracting and repelling neuronal processes as they extend toward their final targets, where guidance cues also play important roles in target recognition and synaptogenesis. During the previous funding period, we identified unique roles for semaphorin cues and their receptors in guiding neuronal processes in both Drosophila and in the mouse, and we also investigated signaling components that serve to facilitate these guidance events. Our cross-phylogenetic approach provides unique insight into select guidance cue-mediated neuronal targeting, and it uses strong complementary experimental strategies. In Drosophila, we have the ability to employ powerful molecular and genetic approaches to address complex aspects of guidance cue function and receptor signaling in vivo. In the mouse, we have the opportunity to employ one of the best characterized laminar structures in the nervous system, the vertebrate retina, to investigate the molecular mechanisms underlying the assembly of complex neuronal connectivity, utilizing powerful genetic and anatomical strategies. Our studies during the previous funding period raise several issues we propose investigating in this renewal application of our long-standing work on semaphorin- mediated neuronal guidance. Our results show that closely related Drosophila secreted semaphorins function through the same receptor to mediate short-range attraction or longer-range repulsion, and we have in place both in vivo and in vitro experimental paridigms that will allow us to begin to dissect critical ligand and receptor signaling interactions that lead to divergent guidance cue responses (Aim I). Our work on mouse transmembrane semaphorin regulation of retinal lamination raises intriguing issues regarding novel mechanisms by which distinct classes of retinal ganglion cells (RGCs) and amacrine cells establish their exquisite connectivity in the IPL, and also how select RGC axonal projections employ transmembrane semaphorins and their plexin receptors to regulate targeting to appropriate retinorecipient CNS targets (Aim II). These studies will contribute to our understanding of circuit assembly and function.

描述（由申请人提供）：神经连接的产生关键取决于神经元过程指导的时间和空间协调调节。该提案的中心目标是了解特定神经元信号蛋白引导线索用于调节轴突和树突靶向的功能和机制。当神经元向最终目标延伸时，一系列线索及其受体在吸引和排斥神经元过程中发挥着关键作用，其中引导线索在目标识别和突触发生中也发挥着重要作用。在之前的资助期间，我们确定了信号蛋白线索及其受体在指导果蝇和小鼠神经元过程中的独特作用，并且我们还研究了促进这些指导事件的信号成分。我们的跨系统发育方法为选择引导线索介导的神经元靶向提供了独特的见解，并且它使用了强大的互补实验策略。在果蝇中，我们有能力采用强大的分子和遗传方法来解决体内引导提示功能和受体信号传导的复杂方面。在小鼠中，我们有机会利用神经系统中特征最鲜明的层状结构之一——脊椎动物视网膜，利用强大的遗传和解剖策略来研究复杂神经元连接组装背后的分子机制。我们在上一个资助期间的研究提出了几个问题，我们建议在我们关于信号蛋白介导的神经元指导的长期工作的更新应用中进行调查。我们的结果表明，密切相关的果蝇分泌的信号蛋白通过相同的受体发挥作用，介导短程吸引或长程排斥，并且我们已经建立了体内和体外实验模型，这将使​​我们能够开始剖析关键的配体和受体信号相互作用导致不同的引导提示反应（目标 I）。我们对小鼠视网膜分层的跨膜信号蛋白调节的研究提出了一些有趣的问题，涉及不同类别的视网膜神经节细胞（RGC）和无长突细胞在 IPL 中建立其精致连接的新机制，以及选择的 RGC 轴突投影如何利用跨膜信号蛋白及其plexin 受体调节靶向适当的视网膜受体中枢神经系统目标 (Aim II)。这些研究将有助于我们 了解电路组装和功能。