Neuropeptides as axonal determinants for oligodendrocyte differentiation and myelination

该提案侧重于解决关于OL生物学的最基本问题之一： 中枢神经系统微环境中的轴突线索控制OL分化和髓鞘形成？趁现在还没有 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 (or两者），我们知道只有轴突-但不是所有的轴突-由OL与神经元平行髓鞘化。 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 根据这一建议，我们已经确定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。神经肽，有几个特点，使他们成为理想的轴突 调节髓鞘形成的信号。它们储存在致密的核心囊泡中，只有在高浓度的 神经元活动水平，这种现象可能标志着一种成熟的形式，使轴突有资格 髓鞘形成神经肽与G蛋白偶联受体结合，具有缓慢作用，可能包括 改变基因表达，提供一种机制，通过这种机制，它们可能改变细胞的命运。本提案中 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.强啡肽是否响应神经元活动而释放以调节髓鞘形成; 3.是否 强啡肽全面影响髓鞘形成或仅限于表达强啡肽的轴突。最近的研究 表明纤维直径、抑制分子和神经元活动的生物物理特性可能都 影响OL前体细胞（OPC）增殖、分化和髓鞘形成轴突的选择（吉布森 等，2014; Hines等人，2015; Mensch等人，2015;雷德蒙等人，2016; Mitew等人，2018; Mayoral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， 神经元亚群，可能是活动依赖性分化和髓鞘形成的基础。我们的初步 数据使我们处于一个独特的位置，以确定强啡肽是否是一种神经肽类， 控制OL分化和髓鞘形成的轴突线索。我们相信这些发现应该会 提供了一个框架，用于识别其他神经肽和递质， 影响少突胶质细胞谱系细胞，以及用于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.