Extracellular Matrix and Axonal Guidance in C. elegans

线虫的细胞外基质和轴突引导

• 批准号: 7812488
• 负责人: WILLIAM G WADSWORTH
• 金额: $ 39万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812488
• 关键词: Acetylcholine; Affect; Alleles; Axon; Biological Models; Caenorhabditis elegans; Complex; Cues; Defect; Development; Disease; Drosophila sax protein; Enhancers; Extracellular Matrix; Genes; Genetic; Genetic Screening; Genetic Techniques; Goals; Growth Cones; Human; Injury; Lead; Link; Maps; Mediating; Modeling; Molecular; Molecular Conformation; Mutate; Mutation; Nerve; Nervous System Physiology; Nervous system structure; Neurons; Organism; Pathway interactions; Pattern; Phenotype; Process; Proteins; Publishing; Recruitment Activity; Regulation; Relative (related person); Role; Signal Pathway; Signal Transduction; Source; Specificity; Surface; System; Testing; Therapeutic Agents; axon guidance; axonal guidance; base; extracellular; gene function; insight; neural circuit; neuron development; neuronal growth; novel; presynaptic; receptor; research study; response; synaptogenesis

Our long-term goal is to find out how migrating axons respond to guidance cues and are guided to their targets. A functional nervous system requires neuronal connections to be made in a highly detailed and stereotypic pattern. This specificity depends on the selection of pathways by neuronal growth cones. We focus on the guidance of specific axons in the C. elegans model system. As in other organisms, including humans, migrating axons have different responses to extracellular guidance cues. We do not have a very good idea of the mechanisms that permit some axon to migrate towards a source of a guidance cue, while other migrate away. How axons change their responsiveness to cues while undergoing morphological changes, such as branching, turning, and synapse formation is also not well understood. Using genetic screens we have identified several molecules likely to regulate axon responses, and now propose to investigate the mechanisms by which they act: (i) We found that in response to UNC-6/netrin and SLT-1/slit guidance cues the axon guidance receptor UNC-40/DCC is asymmetrically localized and recruits proteins such as MIG-10, which can promote axon outgrowth. (ii) UNC-6-ligated UNC-40 is proposed to signal the asymmetric localization of the receptor. We have found mutations in UNC-6 and UNC-40 that may alter the ligated UNC-40 conformation and we are studying how these changes alter the localization of UNC- 40 and can cause outgrowth in different directions. (iii) We found UNC-80 affects axon receptor activity and we are exploring whether this molecules influences the asymmetric localization of receptors relative to the source of the guidance cues. (iv) We have shown that two molecules, CLEC- 38 and RPM-1, negatively regulate the UNC-40 and the UNC-5 and SAX-3 axon guidance receptors, respectively. These molecules also positively regulate presynaptic development, suggesting a link between these processes that could help coordinate their activities. (v) We find evidence that acetylcholine secreted by target neurons regulates axon guidance receptors by controlling CLEC-38 and RPM-1 activity. This signaling could provide a means through which the targets regulate the development of approaching axons. We hope to extend our studies of these different molecules to help elucidate mechanisms that promote specific axon responses to guidance cues, thereby gaining a better understanding of how the neural circuits that underlie nervous system function develop.

我们的长期目标是找出迁移轴突如何响应指导线索，并指导 他们的目标。功能性神经系统需要高度建立神经元连接 详细且刻板印象的模式。该特异性取决于神经元的途径选择 生长锥。我们专注于秀丽隐杆线虫模型系统中特定轴突的指导。如 包括人类在内的其他生物，迁移的轴突对细胞外有不同的反应 指导提示。我们对允许某些轴突的机制没有很好的主意 朝着指导提示的来源迁移，而其他人则迁移。轴突如何改变他们的 在经历形态学变化的同时，对线索的反应，例如分支，转弯和 突触形成也不是很好的理解。使用遗传屏幕，我们已经确定了几个 分子可能调节轴突反应，现在建议通过 他们的作用：（i）我们发现，根据unc-6/netrin和slt-1/slit指南的响应 引导受体UNC-40/DCC是不对称的，募集诸如MIG-10的蛋白质，例如MIG-10， 可以促进轴突的生长。 （ii）提出了UNC-6绑扎的UNC-40，以发出不对称的信号 受体的定位。我们发现在UNC-6和UNC-40中发现突变可能会改变 结扎的UNC-40构象，我们正在研究这些变化如何改变UNC的定位 40，可能会导致不同方向的产物。 （iii）我们发现UNC-80影响轴突受体 活动，我们正在探索该分子是否影响 受体相对于引导线索的来源。 （iv）我们已经证明了两个分子，分子 38和RPM-1，负调节UNC-40和UNC-5和SAX-3轴突引导受体， 分别。这些分子还积极调节突触前发育，表明联系 在这些过程之间可以帮助协调其活动的过程之间。 （v）我们发现证据 靶神经元分泌的乙酰胆碱通过控制CLEC-38来调节轴突引导受体 和RPM-1活性。该信号传导可以提供目标调节目标的手段 开发接近轴突。我们希望将这些不同分子的研究扩展到 帮助阐明促进特定轴突对指导提示的特定轴突响应的机制，从而获得 更好地了解神经系统功能基础的神经回路如何发展。