Investigating the role of a conserved serine/threonine kinase, SAX-1, in higher-order dendrite pruning

研究保守丝氨酸/苏氨酸激酶 SAX-1 在高阶树突修剪中的作用

• 批准号: 10537345
• 负责人: Paola V Figueroa-Delgado
• 金额: $ 4.68万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-01-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537345
• 关键词: Actins; Adult; Afferent Neurons; Alleles; Binding; Biological; Biological Models; Brain; CXCL10 gene; Caenorhabditis elegans; Calcium Signaling; Cells; Cytoskeletal Modeling; Cytoskeleton; Defect; Dendrites; Development; Diapause; Disease; Dorsal; Down Syndrome; Drosophila genus; Ensure; Enzymes; Exposure to; Failure; Genes; Genetic; Genetic Screening; Goals; Image; Larva; Lead; Light; Link; Measures; Mediating; Microtubules; Molecular; Molting; Mus; Nematoda; Nervous system structure; Neurites; Neurodevelopmental Disorder; Neuromuscular Junction; Neurons; Nuclear; Pathway interactions; Phosphotransferases; Process; Property; Protein-Serine-Threonine Kinases; Proteins; Regulation; Reporting; Research; Research Proposals; Resolution; Role; Serine; Shapes; Signal Pathway; Signal Transduction; Sister; Suggestion; System; Testing; Threonine; Work; autism spectrum disorder; innovation; insight; labia; mutant; nervous system development; nervous system disorder; neural circuit; novel; protein protein interaction; recruit; reproductive development; response; scaffold

PROJECT SUMMARY Neurite remodeling is a highly conserved process that refines and establishes a mature nervous system. A failure in neurite remodeling leads to neurological and neurodevelopmental disorders. While developmental dendritic pruning, a means of neurite remodeling, has been extensively studied, the cell-biological mechanisms that control pruning remain poorly understood. Specifically, there is a fundamental gap in understanding how neurons can selectively prune specific dendritic branches while leaving sister branches intact. The long-term goal is to identify and understand the cell-biological mechanisms that direct branch-specific pruning. The nematode Caenorhabditis elegans inner labial 2 (IL2) neurons, upon entering a developmental diapause, extend a stereotypical dendritic arbor that is pruned when development is resumed – leaving primary dendrites intact. The stereotypic remodeling of IL2 neurons allows experimental access to elucidate the cell-biological mechanisms that confer selective pruning. The central hypothesis is that SAX-1, an evolutionarily conversed serine/threonine kinase, functions in a molecular pathway that links calcium signaling to cytoskeletal dynamics in higher-order dendrite branches to direct selective pruning. The rationale for this proposal is that studying the role SAX-1 during IL2 remodeling will offer a framework to understand how local regulation of the cytoskeleton confers branch-specific pruning. The central hypothesis will be tested by the following specific aims: 1) determine how SAX-1 directs pruning of higher-order IL2 dendrite branches; and 2) identify the genetic pathway in which SAX- 1 acts to regulate the cytoskeleton during pruning. The research proposal is innovative because it will 1) be the first to establish C. elegans as a model system for studying pruning, 2) elucidate a novel role for SAX-1 in dendritic pruning, and 3) determine how the cytoskeleton is locally regulated during pruning. The proposed research is significant because elucidating the fundamental cell-biological mechanisms of branch-specific pruning will significantly advance our understanding of developmental neurite remodeling. This understanding is a critical to inform us about how neurodevelopmental processes go awry in disorders such as Down Syndrome.

项目概要 神经突重塑是一个高度保守的过程，可以完善和建立成熟的神经系统。 神经突重塑导致神经系统和神经发育障碍，而发育树突。 修剪是神经突重塑的一种手段，已被广泛研究，其细胞生物学机制 具体来说，对于神经元如何进行控制剪枝的理解还存在根本性的差距。 可以选择性地修剪特定的树突分支，同时保持姐妹分支完好无损。 识别并理解指导特定分支修剪的细胞生物学机制。 秀丽隐杆线虫内唇 2 (IL2) 神经元在进入发育滞育后，会延长 典型的树突乔木，在恢复发育时被修剪，使初生树突保持完整。 IL2 神经元的刻板重塑允许通过实验阐明细胞生物学机制 赋予选择性修剪的核心假设是SAX-1，一种进化上转换的丝氨酸/苏氨酸。 激酶，在将钙信号传导与高阶细胞骨架动力学联系起来的分子途径中发挥作用 该提案的基本原理是研究 SAX-1 的作用。 IL2 重塑期间的研究将提供一个框架来了解细胞骨架的局部调节如何赋予 特定分支的修剪将通过以下具体目标进行检验：1）确定如何修剪。 SAX-1 指导高阶 IL2 树突分支的修剪；2) 识别 SAX-1 的遗传途径 1 在修剪过程中发挥调节细胞骨架的作用 该研究提案具有创新性，因为它 1) 是 首先建立了秀丽隐杆线虫作为研究修剪的模型系统，2）阐明了 SAX-1 在修剪中的新作用 树突修剪，3）确定细胞骨架在修剪过程中如何局部调节。 研究意义重大，因为阐明了分支特异性的基本细胞生物学机制 修剪将显着增进我们对发育性神经突重塑的理解。 对于让我们了解唐氏综合症等疾病的神经发育过程如何出错至关重要。