SKAP2 as a new regulator of oligodendroglial migration and myelin sheath formation
SKAP2 as a new regulator of oligodendroglial migration and myelin sheath formation
复制标题
DOI：
10.1002/glia.24066
复制
发表时间：
2021-07-29
期刊：
影响因子：
6.2
通讯作者：
Kuhlmann, Tanja
中科院分区：
文献类型：
--
作者：
Ghelman, Julia;Grewing, Laureen;Kuhlmann, Tanja
少突胶质祖细胞（Oligodendunglialprogenitorcells，OPCs）是一种高度增殖和迁移的细胞，在髓鞘形成过程中分化为复杂的髓鞘形成和轴突鞘化的成熟少突胶质细胞。最近的研究表明，少突胶质细胞群体在转录和功能水平上是异质性的，这取决于在中枢神经系统中的位置。在此，我们从功能和转录水平上比较了脊髓和脑OPC的内在特性。脊髓OPC表现出增加的迁移以及分化能力。此外，转录组分析揭示了两个OPC群体之间的几个基因的差异表达。在脊髓OPC中，我们证实了SKAP 2的上调，SKAP 2是一种细胞质衔接蛋白，以其在其他细胞类型中的细胞骨架重塑和迁移中的作用而闻名。最近的研究结果表明，肌动蛋白动力学不仅决定少突胶质细胞的迁移，但也分化：而肌动蛋白聚合是重要的过程的延伸，肌动蛋白的不稳定和解聚是髓鞘形成所需的。OPC中SKAP 2的下调或完全缺乏导致少突胶质细胞迁移减少和形态成熟受损。相反，SKAP 2的过表达以及组成型活性SKAP 2增加OPC迁移，表明SKAP 2功能依赖于磷酸化激活。此外，缺乏SKAP 2增强了整合素活化后对OPC迁移的积极作用，表明SKAP 2充当整合素依赖性迁移的调节剂。总之，我们证明了脊髓和脑OPC之间存在内在差异，并确定SKAP 2作为少突胶质细胞迁移和鞘形成的新调节因子。
Oligodendroglial progenitor cells (OPCs) are highly proliferative and migratory cells, which differentiate into complex myelin forming and axon ensheathing mature oligodendrocytes during myelination. Recent studies indicate that the oligodendroglial cell population is heterogeneous on transcriptional and functional level depending on the location in the central nervous system. Here, we compared intrinsic properties of OPC from spinal cord and brain on functional and transcriptional level. Spinal cord OPC demonstrated increased migration as well as differentiation capacity. Moreover, transcriptome analysis revealed differential expression of several genes between both OPC populations. In spinal cord OPC, we confirmed upregulation of SKAP2, a cytoplasmatic adaptor protein known for its implication in cytoskeletal remodeling and migration in other cell types. Recent findings suggest that actin dynamics determine not only oligodendroglial migration, but also differentiation: Whereas actin polymerization is important for process extension, actin destabilization and depolymerization is required for myelin sheath formation. Downregulation or complete lack of SKAP2 in OPC resulted in reduced migration and impaired morphological maturation in oligodendrocytes. In contrast, overexpression of SKAP2 as well as constitutively active SKAP2 increased OPC migration suggesting that SKAP2 function is dependent on activation by phosphorylation. Furthermore, lack of SKAP2 enhanced the positive effect on OPC migration after integrin activation suggesting that SKAP2 acts as modulator of integrin dependent migration. In summary, we demonstrate the presence of intrinsic differences between spinal cord and brain OPC and identified SKAP2 as a new regulator of oligodendroglial migration and sheath formation.