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: 10217979
• 负责人: BING YE
• 金额: $ 38.17万
• 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/10217979
• 关键词: 3' Untranslated Regions; 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发育成不同的形态——这是组装的基础 神经回路的结构——人们对区分树突和轴突的机制知之甚少。 因此，发育是发育神经科学的一个重要目标。 致力于树突特异性或轴突特异性体内生长已通过利用 此外，抑制树突生长但促进轴突生长的分子途径。 同一神经元内的生长（即双峰机制）已位于这些专用的上游 双峰调控提供了产生形态多样性的独特机制。 神经元，并且与设计再生受伤或患病神经的有效策略相关 这项研究的长期目标是确定神经元如何发育成不同的亚细胞部分。 以及这个过程中的缺陷如何导致人类疾病。拟议研究的目的是揭示这一过程的缺陷。 最近的研究已经揭示了树突和轴突生长双模式控制的分子和细胞机制。 研究表明，进化上保守的双亮氨酸拉链激酶/Wallenda (DLK/Wnd) 途径是双峰的 树突和轴突生长的调节因子，并且该途径调节转录的表达水平 因子（Knot）和细胞粘附分子（Dscam）分别控制树突和轴突的生长。 初步研究提出了一个新概念：通过 RNA 结合蛋白进行翻译调控 树突和轴突生长双模式控制的核心以下模型集成了特定分子。 以及双峰控制空间位置的法规将受到测试：DLK/Wnd 途径调节 两种不同的 RNA 结合蛋白控制轴突末端 Dscam 翻译的 PABP 依赖性启动 该模型将分别用于轴突生长和细胞体中的结表达用于树突生长。 通过确定 (a) DLK/Wnd 通路调节轴突末端的分子机制进行测试 发育和树突分支发育以及 (b) DLK/Wnd 的亚细胞位置 途径调节下游因子来指导树突和轴突的差异生长。 研究具有创新性，因为它提出了树突差异发育的新概念 轴突并采用了几种非常适合该研究领域的创新技术。 意义重大，因为它有望为树突和轴突之间的协调提供重要的见解 发育，确定翻译控制在树突差异发育中发挥的关键作用， 轴突，发现 DLK/Wnd 通路在神经元中发挥作用的新机制，并提供见解 神经发育障碍的发病机制。