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的轴突如何对引导线索做出反应，并被引导到 他们的目标。一个有功能的神经系统需要高度的神经元连接 细节和刻板的模式。这种特异性依赖于神经元对通路的选择 生长锥体。我们专注于线虫模型系统中特定轴突的指导。如中所示 其他生物，包括人类，迁移的轴突对细胞外有不同的反应 引导线索。我们对允许某些轴突的机制并不是很了解 向指导线索的来源迁移，而其他人则迁移离开。轴突是如何改变它们的 在经历形态变化时对暗示的反应，如分枝、转弯和 突触的形成也不是很清楚。使用基因筛查，我们已经确定了几个 可能调节轴突反应的分子，现在建议通过 他们的行为：(I)我们发现，作为对UNC-6/netrin和SLT-1/Sit的反应，轴突 引导受体UNC-40/DCC不对称定位并募集MIG-10等蛋白质， 这可以促进轴突的生长。(Ii)建议使用UNC-6连接的UNC-40作为不对称信号 受体的定位。我们已经在UNC-6和UNC-40中发现了可能改变 连接了UNC-40构象，我们正在研究这些变化如何改变UNC-40的定位- 40岁，并可能导致不同方向的生长。(Iii)我们发现UNC-80影响轴突受体 活性，我们正在探索这种分子是否会影响不对称局部化 相对于引导线索来源的感受器。(Iv)我们已经证明了两个分子，ClEc- 38和RPM-1，负性调节UNC-40以及UNC-5和SAX-3轴突引导受体， 分别进行了分析。这些分子也积极地调节突触前发育，这表明 这些进程之间的联系可以帮助协调他们的活动。(V)我们发现有证据表明 靶神经元分泌的乙酰胆碱通过调控CLEC-38调节轴突导向受体 和RPM-1活性。这种信号可以提供一种手段，通过这种手段，目标可以调节 接近轴突的发育。我们希望将我们对这些不同分子的研究扩展到 帮助阐明促进特定轴突对引导线索的反应的机制，从而获得 更好地了解构成神经系统功能的神经回路是如何发展的。