Neuropeptides as axonal determinants for oligodendrocyte differentiation and myelination

这项建议侧重于解决关于OL生物学的一个最基本的问题：什么 中枢神经系统微环境中的轴突信号控制OL分化和髓鞘形成？趁它还在的时候 不清楚髓鞘形成的空间和时间模式是依赖于诱导性还是抑制性线索 (或两者兼而有之)，我们知道只有轴突--但不是所有的轴突--是由与神经元平行的OL髓鞘形成的 电路成熟。这表明轴突衍生的信号必须参与协调这一过程。在……里面 在这一提议中，我们已经确定了一类新的轴突衍生多肽，即促进OL的强啡肽 分化和髓鞘形成。神经肽，有几个特征使它们成为理想的轴突 调节髓鞘形成的信号。它们储存在致密的核心囊泡中，只有在高密度时才会释放 神经元活动水平，这一现象可能标志着一种形式的成熟，使轴突有资格 髓鞘形成。神经肽与G蛋白偶联受体结合，具有慢作用，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。在本建议书中 我们将调查：1.OL及其前体是否受神经肽类强啡肽的影响， 2.强啡肽是否因神经元活动而释放，以调节髓鞘形成；3.强啡肽是否 强啡肽在全球范围内影响髓鞘形成，或仅限于强啡肽表达轴突。最新研究 证明了纤维直径、抑制分子和神经元活性的生物物理特性 影响OL前体细胞(OPC)的增殖、分化和髓鞘轴突的选择(吉布森 等人，2014年；Hines等人，2015年；Mensch等人，2015年；Redmond等人，2016年；Mitew等人，2018年；Mayole等人， 2018年)。在这里，我们提供了一个特定的分子机制和下游信号通路 神经元的一个子集，可能构成依赖活动的分化和髓鞘形成的基础。我们的预赛 数据使我们处于一个独特的位置来确定强啡肽是否是代表 控制OL分化和髓鞘形成的轴突线索。我们认为，这些调查结果应该给予 为识别额外的神经肽和递质提供了有价值的见解，这些神经肽和递质可能 影响少突胶质系细胞，以及分析髓鞘形成的抑制和诱导线索。

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.