Characterizing Novel Regulations of Dendritic Tiling in C. elegans

表征秀丽隐杆线虫树突平铺的新调控

• 批准号: 10204136
• 负责人: Meera P Trivedi
• 金额: $ 1.52万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204136
• 关键词: Ablation; Alleles; Axon; Bilateral; Binding; Biological Models; Biological Process; Caenorhabditis elegans; Candidate Disease Gene; Cells; Characteristics; Complex; Cues; Data; Defect; Dendrites; Development; Diagnostic; Disease; Drosophila genus; Foundations; Genes; Genetic; Genetic Screening; Goals; Head; Image; Lasers; Lesion; Longevity; Mediator of activation protein; Microtubules; Modeling; Molecular; Morphology; Mutation; Nematoda; Nervous system structure; Neurites; Neurodevelopmental Disorder; Neurons; Pathology; Pathway interactions; Process; Property; Protein Family; Proteins; Regulation; Research; Retinal Ganglion Cells; Role; Schizophrenia; Semaphorin-3A; Sensory; Specific qualifier value; Stereotyping; Structure; Study models; Sum; Synapses; Techniques; Testing; Therapeutic; Time; Tubulin; autism spectrum disorder; comparative; experimental study; genetic approach; insight; knock-down; member; mutant; neural circuit; neurodevelopment; neuropsychiatric disorder; novel; receptive field; response; time use

PROJECT SUMMARY Neurons rely on dendrites for the acquisition of sensory and synaptic input from their particular receptive fields. Findings of aberrant dendritic morphology in disorders such as autism spectrum disorder (ASD) and schizophrenia highlight the importance of understanding how complex dendritic arbors are developed and maintained. During development, one of the goals of dendritic outgrowth is non-redundant coverage of a receptive field, which requires the avoidance of other dendrites both from the same neuron (self-avoidance) and from others (tiling). Tiling is evident in the organization of sensory neurites, such as those of C. elegans mechanosensory neurons, drosophila dendritic arborization (da) neurons, and vertebrate retinal ganglion cells. While tiling is a conserved property of many nervous systems, the molecular mechanisms by which it is established remain unclear. The goal of this project is to uncover the genetic and molecular mechanisms of dendritic tiling using the multi-dendritic FLP and PVD mechanosensory neurons of C. elegans as a model. The dendritic arbor of FLP covers the head of the worm while the arbor of PVD covers the body. While previous studies have identified both cell autonomous and cell non-autonomous cues for self-avoidance in outgrowing PVD dendrites, the mechanisms by which FLP and PVD establish distinct non-overlapping receptive fields remains unknown. From a pilot forward genetic screen, I have identified unc-33 as a gene required for the specification of FLP and PVD receptive field size. Unc-33 is a member of the Collapsin Response Mediator Protein (CRMP) family and is known to regulate axon development through the organization of microtubules. While the role of unc-33 in axon outgrowth is well-characterized, its role in dendritic tiling is unclear. In the first Aim of this project, I will use time-lapse imaging and cell ablation experiments to characterize the normal development of tiling between FLP and PVD neurons. In the second Aim of this project, I will use genetic and molecular techniques to determine the mechanism of action of unc-33 in regulating FLP and PVD tiling. In the third Aim of this project, I will use a combined candidate and forward genetic approach to identify novel regulators of tiling between FLP and PVD neurons. The results from this project will establish FLP and PVD as a new model for the study of dendritic tiling and identify novel pathways regulating this process. Understanding the basic mechanisms for the development for dendritic morphology will provide a foundation from which to understand how these mechanisms are altered in neurodevelopmental disorders.

项目总结 神经元依靠树突从其特定的感受野获得感觉和突触输入。 自闭症谱系障碍(ASD)等疾病树突状细胞异常形态的研究 精神分裂症突出了了解复杂的树枝是如何形成和发展的重要性 维护好了。在开发期间，树枝状扩展的目标之一是无冗余地覆盖 感受野，这需要避免来自同一神经元的其他树突(自我回避)和 来自其他人(平铺)。瓦片在感觉神经突起的组织中很明显，例如线虫的那些 机械感觉神经元、果蝇树突状树枝(Da)神经元和脊椎动物视网膜神经节细胞。 虽然瓷砖是许多神经系统的保守属性，但它的分子机制 是否成立仍不清楚。这个项目的目标是揭示人类免疫缺陷的遗传和分子机制。 以线虫多树突状FLP和PVD机械感觉神经元为模型的树突平铺。这个 FLP的树枝覆盖在虫头上，PVD的树枝覆盖在身体上。而上一次 研究已经确定了细胞自主和细胞非自主暗示在外延生长中的自我回避 PVD树突，FLP和PVD建立不同的非重叠感受野的机制 仍然不为人知。从飞行员的前向基因筛查中，我已经确定UNC-33是 FLP和PVD接收场大小的规范。UNC-33是崩溃反应调解人的成员 蛋白(CRMP)家族，已知通过微管的组织来调节轴突的发育。 虽然UNC-33在轴突生长中的作用已经被很好地描述，但它在树突状瓦片中的作用尚不清楚。在第一个 本项目的目的是，我将使用时间推移成像和细胞消融实验来表征正常 FLP和PVD神经元之间的瓦片发育。在这个项目的第二个目标中，我将使用基因和 用分子技术确定UNC-33调节FLP和PVD瓷砖的作用机制。在 这个项目的第三个目标是，我将使用候选基因和正向基因相结合的方法来识别新的调节子 FLP和PVD神经元之间的瓦片。该项目的结果将使FLP和PVD成为一种新的模式 用于树枝状瓷砖的研究，并确定调控这一过程的新途径。了解基本知识 树枝状形态发育的机制将提供一个理解的基础 这些机制在神经发育障碍中是如何改变的。