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：
10526408
负责人：
Jonah R Chan
金额：
$ 40.01万
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/10526408
关键词：
Address Adult Affect Axon Behavior Binding Biology CSPG4 gene Cell Differentiation process Cell Lineage Cell Proliferation Cells Characteristics Coculture Techniques Complex Corpus striatum structure Cre driver Cues Data Dense Core Vesicle Development Diameter 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 Membrane Minor Molecular Mus Muscarinics Myelin Neurons Neuropeptides Oligodendroglia Opioid agonist Pathway interactions Pattern Peptides Phenocopy Population Positioning Attribute Process Qualifying Receptor Activation Reporter Selective Estrogen Receptor Modulators Signal Pathway Signal Transduction Stress Swimming Visualization acute stress antagonist 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 precursor p38 Mitogen Activated Protein Kinase postnatal precursor cell response small molecule tau Proteins

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.

该提案重点解决有关 OL 生物学的最基本问题之一：什么 CNS微环境中的轴突线索控制OL分化和髓鞘形成？不清楚髓鞘形成的空间和时间模式是否依赖于诱导或抑制线索（或两者），我们知道只有轴突——但不是所有轴突——与神经元并行地由 OL 形成髓鞘。这表明轴突衍生的信号必须参与协调这一过程。根据这项提议，我们发现了一种新的轴突衍生肽类，即促进 OL 的强啡肽分化和髓鞘形成，具有使其成为理想轴突的几个特征。它们储存在致密的核心囊泡中，仅在高浓度时释放。神经活动水平，这种现象可能标志着轴突成熟的一种形式神经肽与 G 蛋白偶联受体结合并具有缓慢作用，可能包括改变基因表达，提供一种可能改变细胞命运的机制。我们将研究： 1. OL 及其前体是否受到神经肽类强啡肽的影响 2. 强啡肽是否会响应神经活动而释放以调节髓鞘形成，以及 3. 是否强啡肽影响整体髓鞘形成或仅限于表达强啡肽的轴突。证明纤维直径、抑制分子和神经元活动的生物物理特性都可能影响 OL 前体细胞 (OPC) 增殖、分化和髓鞘形成轴突的选择 (Gibson 等人，2014；Mensch 等人，2015；Mitew 等人，2018； 2018），我们提供了特定的分子机制和下游信号通路。可能是活动依赖性分化和髓鞘形成的基础的神经元子集。数据使我们处于一个独特的位置，可以确定强啡肽是否是代表的神经肽类我们相信这些发现应该传递出控制 OL 分化和髓鞘形成的轴突线索。提供了一个框架来识别额外的神经肽和递质，这些神经肽和递质可能具有宝贵的见解影响少突胶质细胞系细胞，以及分析髓鞘形成的抑制和诱导线索。