Mechanisms that differentiate dendrite development from axon development

区分树突发育和轴突发育的机制

• 批准号: 9446382
• 负责人: BING YE
• 金额: $ 38.12万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9446382
• 关键词: 3' Untranslated Regions; Alpha Cell; Axon; Axonal Transport; Binding Proteins; Biochemical Genetics; Biological; Cell Adhesion Molecules; Cell Nucleus; Cell Size; Cells; Defect; Dendrites; Development; Down Syndrome Cell Adhesion Molecule; Drosophila genus; Dynein ATPase; Goals; Growth; Heterogeneous-Nuclear Ribonucleoproteins; Knowledge; Label; Larva; Lead; Leucine Zippers; Location; Mediating; Mental disorders; Mission; Modeling; Molecular; Molecular Genetics; Morphology; Natural regeneration; Nerve Degeneration; Nerve Regeneration; Neurodevelopmental Disorder; Neurons; Neurosciences; Pathogenesis; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Poly(A)-Binding Proteins; Presynaptic Terminals; Process; Proteins; Proteomics; Public Health; RNA interference screen; RNA-Binding Proteins; Regulation; Research; Role; Signal Transduction; Specificity; System; Techniques; Testing; Translational Regulation; Translations; United States National Institutes of Health; Work; axon growth; base; design; genetic approach; human disease; improved; in vivo; injured; innovation; insight; nervous system disorder; neural circuit; neuron development; newborn neuron; novel; retrograde transport; transcription factor

How a neuron’s dendrites and axons develop into distinct morphology—which is fundamental to the assembly of neural circuits—is poorly understood. Understanding the mechanisms that differentiate dendrite and axon development, therefore, is a vital goal in developmental neuroscience. Several regulatory mechanisms that are dedicated to either dendrite-specific or axon-specific growth in vivo have been identified by taking advantage of a Drosophila system. In addition, a molecular pathway that suppresses dendritic growth but promotes axonal growth within the same neuron (i.e., a bimodal mechanism) has been located upstream of these dedicated mechanisms. The bimodal regulation provides a unique mechanism for generating morphological diversity in neurons, and is relevant for the design of effective strategies to regenerate an injured or diseased nervous system. The long-term goal of this research is to define how a neuron develops into distinct subcellular parts and how defects in this process lead to human disease. The objective of the proposed studies is to uncover the molecular and cellular mechanisms of bimodal controls of dendritic and axonal growth. Recent studies have shown that the evolutionarily conserved dual leucine zipper kinase/Wallenda (DLK/Wnd) pathway is a bimodal regulator of dendritic and axonal growth, and that this pathway regulates the expression levels of a transcription factor (Knot) and a cell adhesion molecule (Dscam) to control dendritic and axonal growth, respectively. Preliminary studies suggest a novel concept: Translational regulation through RNA-binding proteins is at the core of bimodal control of dendritic and axonal growth. The following model, which integrates specific molecules and regulations with their spatial locations for bimodal control, will be tested: The DLK/Wnd pathway regulates two distinct RNA-binding proteins to control PABP-dependent initiation of Dscam translation in axon terminals for axonal growth and Knot expression in the cell body for dendritic growth, respectively. This model will be tested by identifying (a) the molecular mechanism by which the DLK/Wnd pathway regulates axon-terminal development and dendritic branch development and (b) the subcellular locations at which the DLK/Wnd pathway regulates downstream factors to instruct the differential growth of dendrites and axons. The proposed research is innovative because it proposes a novel concept in the differential development of dendrites and axons and employs several innovative techniques that are well suited for this line of research. This research is significant because it is expected to offer key insights into the coordination between dendritic and axonal development, identify a critical role translational control plays in the differential development of dendrites and axons, discover novel mechanisms by which the DLK/Wnd pathway functions in neurons, and provide insights into the pathogenesis of neurodevelopmental disorders.

神经元的树突和轴突如何形成独特的形态 - 这是大会的基础 神经回路的理解很少。了解区分树突和轴突的机制 因此，发展是发育神经科学的至关重要目标。几种监管机制 通过利用优势，已经确定了专用于体内树突特异性或轴突特异性生长 果蝇系统。另外，一种抑制树突生长但促进轴突的分子途径 同一神经元内的生长（即双峰机制）已位于这些专用的上游 机制。双峰调节提供了一种独特的机制，可以产生形态学多样性 神经元，与设计有效策略的设计有关 系统。这项研究的长期目标是定义神经元发展如何分为不同的亚细胞部件 以及此过程中的缺陷如何导致人类疾病。拟议研究的目的是发现 树突状生长和轴突生长的双峰对照的分子和细胞机制。最近的研究 表明进化构成双亮氨酸拉链激酶/wallenda（DLK/WND）途径是双峰 树突状和轴突生长的调节剂，该途径调节转录的表达水平 因子（结）和细胞粘附分子（DSCAM）分别控制树突状和轴突生长。 初步研究表明了一个新颖的概念：通过RNA结合蛋白的翻译调节是 树突状和轴突生长的双峰控制的核心。以下模型，该模型整合了特定分子 和及其双峰控制空间位置的法规将进行测试：DLK/WND途径调节 两种不同的RNA结合蛋白控制轴突终端中DSCAM翻译的PABP依赖性计划 分别用于细胞体中的轴突生长和结的结。分别用于树突状生长。这个模型将是 通过识别（a）DLK/WND途径调节轴突末端的分子机制测试 开发和树突分支的发展以及（b）DLK/WND的亚细胞位置 途径调节下游因素以指导树突和轴突的差异生长。提议 研究具有创新性，因为它提出了一个新颖的概念，该概念在树突的差异发展和 轴突和员工非常适合这一研究的创新技术。这项研究是 重要的是因为预计它将对树突状和轴突之间的协调提供关键的见解 开发，确定转化控制在树突的差异发展中的关键作用和 轴突，发现DLK/WND途径在神经元中起作用并提供见解的新型机制 进入神经发育障碍的发病机理。