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How do non-myelinating glia ensheath axons?

非髓鞘神经胶质细胞如何包裹轴突？

基本信息

批准号：
10397991
负责人：
Marc R Freeman
金额：
$ 33.69万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397991
关键词：
Address Affect Automobile Driving Axon Behavioral Assay Binding Biochemical Biological Assay Biology Cell Surface Receptors Cells Cellular biology Clinical Collagen Collagen Receptors Collagen Type XVIII Collection Communication Complex Data Defect Development Disease Dominant Genetic Conditions Drosophila genome Drosophila genus Endostatins Epidermal Growth Factor Receptor Exhibits Expression Profiling Fiber Fibroblast Growth Factor Receptors Genes Genetic Health Homologous Gene Human Impairment Individual Injury Integrin beta Chains Invertebrates Ligands Maintenance Mammals Mediating Membrane Metabolic Modeling Molecular Molecular Genetics Multiple Sclerosis Mus Myelin Nerve Nervous System Physiology Nervous system structure Neuroglia Neurons Neuropathy Oligodendroglia Orthologous Gene Pain Pathway interactions Peripheral Peripheral Nerves Peripheral Nervous System Peripheral Nervous System Diseases Phase Phenotype Physiological Physiology Process RNA Interference RNA interference screen Reagent Receptor Protein-Tyrosine Kinases Receptor Signaling Role Schwann Cells Sensory Signal Pathway Signal Transduction Signaling Molecule Structure Testing Vertebrates Work autocrine discoidin receptor fly glial cell development in vivo insight intercellular communication interest knock-down leukodystrophy molecular array mouse model mutant myelination neurotransmission novel receptor receptor function remyelination tool

项目摘要

Project summary Glial ensheathment of axons is a conserved feature of nervous systems that is essential for proper nervous system function. Impairment or loss of axonal wrapping underlies many debilitating conditions including multiple sclerosis, leukodystrophies, peripheral neuropathies, and CMT diseases. Despite many years of work our understanding of the molecular pathways that control glial development, glial-axon communication, and ensheathment of long axons, including myelination, is far from complete. Our understanding of non-myelinating forms of axon ensheathment is particularly sparse, despite the fact that the majority of peripheral axons (~70%) in humans are unmyelinated and encased by Remak Schwann cells. To address this gap in our understanding we propose to use the genetically tractable model Drosophila to characterize novel molecular mechanisms that promote glial ensheathment of axons and to study the functional roles of non-myelinating ensheathment in axon health and function in vivo. In Drosophila, specialized glia called wrapping glia (WG) ensheath peripheral axons in a manner closely resembling vertebrate Remak SCs. Recent studies (including our own preliminary data) have found that many genes that control the formation of vertebrate myelin also control axon ensheathment by WG in the fly, supporting strong molecular conservation between these forms of ensheathment. We have taken advantage of the fly to conduct a large-scale RNAi screen for novel regulators of ensheathment, and have identified a number of exciting new genes required for glial ensheathment of axons. One candidate to emerge from the screen, discoidin domain receptor (Ddr), encodes an evolutionarily conserved receptor tyrosine kinase activated by collagens. We show that loss of Ddr in WG results in profound defects in axonal ensheathment: although WG can grow longitudinally along the nerve they fail to insert processes between bundled axons to sort and ensheath them. Intriguingly, murine Ddr1 is highly expressed in oligodendrocytes and detailed expression profiling reveals that mDdr1 expression increases at the onset of wrapping during development and with the initiation of remyelination after injury, but functional roles for mDdr in ensheathment or myelination has not been investigated. Our preliminary work has also identified the Type XV/XVIII collagen homolog Multiplexin as required for axon ensheathment, possibly by acting as a ligand for Ddr. In Aim 1 we will characterize the role of Ddr in promoting axonal ensheathment, determine its autonomy of action, and perform a structure function analysis to define key aspects of Ddr signaling in vivo. In Aim 2 we will investigate the role of Mp in driving ensheathment and directly test our model that Mp acts in an autocrine fashion to activate the Ddr receptor on WG. Finally, in Aim 3 we will take advantage of the many genes identified in the screen that have mild to strong ensheathment defects to probe the function of non-myelinating ensheathment on neuronal health and physiology using behavioral assays and in vivo physiological studies. Our work will define the mechanistic basis of Ddr and Mp signaling during nerve assembly and glial ensheathment of axons, and help define the enigmatic but essential functions of non-myelinating forms of ensheathment in complex nervous systems.

项目总结