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Mechanisms that differentiate dendrite development from axon development

区分树突发育和轴突发育的机制

基本信息

批准号：
9982446
负责人：
BING YE
金额：
$ 38.21万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/9982446
关键词：
3&apos 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

项目摘要

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是如何形成不同的形态的