Molecular heterogeneity of oligodendrocytes: novel role and regional relevance of a chemokine-like signaling protein in brain function

CNS髓鞘由成熟的少突胶质细胞提供，其在形态和电生理特性方面显示出区域异质性。然而，潜在的分子遗传多样性尚未报道。我们推测，区域少突胶质细胞的异质性反映在分子水平上的蛋白质组成的髓鞘。在初步实验中，我们使用定量质谱法来确定从健康小鼠大脑的各个区域纯化的髓鞘的蛋白质组。虽然主要结构髓磷脂蛋白（如PLP或MOG）的丰度在所分析的脑区域中基本相似，但几种非结构蛋白显示出相当大的丰度异质性，例如，与皮质下白色物质相比，来自皮质灰质的髓磷脂。为了选择蛋白质进行更详细的分析，我们评估了我们的数据集，以获得在细胞代谢或细胞间信号传导中可能具有功能的异质丰富的髓鞘蛋白。在一个试点实验中，我们确定了CMTM 5（趋化因子样因子MARVEL transmembrane-domain containing protein 5），并在基因上删除了其在少突胶质细胞中的表达。基于我们未发表的观察结果，我们将检验CMTM 5不参与髓鞘本身的生物发生，但参与少突胶质细胞向有髓鞘轴突的信号传导的假设。该项目将涉及生物化学/蛋白质组学、小鼠遗传学、电子显微镜和小鼠行为评估。我们预计，信号蛋白，如CMTM 5有助于建立区域不同的功能的少突胶质细胞，这一新的概念将在体内进行测试。

CNS myelin is provided by mature oligodendrocytes, which display regional heterogeneity with respect to morphology and electrophysiological properties. However, underlying molecular-genetic diversity has not been reported. We hypothesized that regional oligodendrocytic heterogeneity is reflected at the molecular level in the protein composition of myelin. In pilot experiments, we have used quantitative mass spectrometry to determine the proteome of myelin purified from various regions of healthy mouse brains. While the abundance of major structural myelin proteins, such as PLP or MOG, is largely similar across the analyzed brain regions, several non-structural proteins display considerable heterogeneity of abundance, e.g. in myelin from the cortical gray matter compared to the subcortical white matter. To select proteins for more detailed analysis, we have evaluated our datasets for heterogeneously abundant myelin proteins with a probable function in cellular metabolism or intercellular signaling. In a pilot experiment, we identified CMTM5 (chemokine-like factor MARVEL transmembrane-domain containing protein 5) and genetically deleted its expression specifically in oligodendrocytes. Based on our unpublished observations we will test the hypothesis that CMTM5 is not involved in the biogenesis of myelin per se but in oligodendrocytic signaling to myelinated axons. This project will involve biochemistry/proteomics, mouse genetics, electron microscopy and assessment of mouse behaviour. We anticipate that signaling proteins such as CMTM5 contribute to establishing regionally distinct functions of oligodendrocytes; this novel concept will be tested in vivo.