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Neuropeptides as axonal determinants for oligodendrocyte differentiation and myelination

神经肽作为少突胶质细胞分化和髓鞘形成的轴突决定因素

基本信息

批准号：
10132642
负责人：
Jonah R Chan
金额：
$ 39.84万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10132642
关键词：
Address Adult Affect Axon Behavior Binding Biology CSPG4 gene Caliber Cell Differentiation process Cell Lineage Cell Proliferation Cells Characteristics Coculture Techniques Complex Corpus striatum structure Cre driver Cues Data Dense Core Vesicle Development Dose Dynorphins FRAP1 gene Fiber G-Protein-Coupled Receptors Gene Expression Gene Expression Profiling Generations Genetic Recombination Histologic In Vitro Interneurons Knockout Mice Label MAP Kinase Gene MAPK3 gene Mediating Mediator of activation protein Membrane Minor Molecular Mus Muscarinics Myelin Neurons Neuropeptides Oligodendroglia Opioid agonist Pathway interactions Pattern Peptides Phenocopy Population Positioning Attribute Process Receptor Activation Reporter Selective Estrogen Receptor Modulators Signal Pathway Signal Transduction Stress Swimming acute stress base biophysical properties designer receptors exclusively activated by designer drugs extracellular high throughput screening insight kappa opioid receptors myelination neuronal cell body neuronal circuitry neurotransmission novel oligodendrocyte myelination oligodendrocyte precursor p38 Mitogen Activated Protein Kinase postnatal precursor cell response small molecule tau Proteins vesicular release

项目摘要

This proposal focuses on addressing one of the most fundamental questions regarding OL biology: What axonal cues in the CNS microenvironment control OL differentiation and myelination? While it is still yet unclear whether the spatial and temporal patterns of myelination are dependent on inductive or inhibitory cues (or both), we know that exclusively axons – but not all axons – are myelinated by OLs in parallel with neuronal circuit maturation. This suggests that axon-derived signals must be involved in coordinating this process. In this proposal, we have identified a novel axon-derived peptide class, namely dynorphins that promote OL differentiation and myelination. Neuropeptides, have several characteristics that make them an ideal axonal signal to regulate myelination. They are stored in dense core vesicles and released only in response to high levels of neuronal activity, a phenomenon that might signal a form of maturation that qualifies an axon for myelination. Neuropeptides bind to G-protein coupled receptors and have slow-acting effects that may include altering gene expression, providing a mechanism through which they might alter cellular fate. In this proposal we will investigate: 1. Whether OLs and their precursors are influenced by the neuropeptide class, dynorphin, 2. Whether dynorphins are released in response to neuronal activity to regulate myelination and 3. Whether dynorphins influence myelination globally or is restricted only to dynorphin expressing axons. Recent studies demonstrate that biophysical properties of fiber diameter, inhibitory molecules and neuronal activity may all affect OL precursor cell (OPC) proliferation, differentiation, and the selection of axons for myelination (Gibson et al., 2014; Hines et al., 2015; Mensch et al., 2015; Redmond et al., 2016; Mitew et al., 2018; Mayoral et al., 2018). Here, we provide the molecular mechanism and downstream signaling pathways for a specific subset of neurons that may underlie activity dependent differentiation and myelination. Our preliminary data place us in a unique position to determine whether dynorphins are a neuropeptide class that represents an axonal cue to control OL differentiation and myelination. We believe that these findings should impart valuable insight in providing a framework for identifying additional neuropeptides and transmitters that may influence oligodendroglial lineage cells, as well as for profiling inhibitory and inductive cues for myelination.

本提案的重点是解决OL生物学中最基本的问题之一：什么