Department of Cell and Developmental Biology and.
Cell Biology, Stem Cells, and Development Graduate Program, University of Colorado School of Medicine, Aurora, Colorado 80045.
J Neurosci. 2021 Mar 3;41(9):1864-1877. doi: 10.1523/JNEUROSCI.0229-20.2021. Epub 2021 Jan 21.
The actin cytoskeleton is crucial for oligodendrocyte differentiation and myelination. Here we show that p21-activated kinase 1 (PAK1), a well-known actin regulator, promotes oligodendrocyte morphologic change and myelin production in the CNS. A combination of and models demonstrated that PAK1 is expressed throughout the oligodendrocyte lineage with highest expression in differentiated oligodendrocytes. Inhibiting PAK1 early in oligodendrocyte development decreased oligodendrocyte morphologic complexity and altered F-actin spreading at the tips of oligodendrocyte progenitor cell processes. Constitutively activating AKT in oligodendrocytes in male and female mice, which leads to excessive myelin wrapping, increased PAK1 expression, suggesting an impact of PAK1 during active myelin wrapping. Furthermore, constitutively activating PAK1 in oligodendrocytes in zebrafish led to an increase in myelin internode length while inhibiting PAK1 during active myelination decreased internode length. As myelin parameters influence conduction velocity, these data suggest that PAK1 may influence communication within the CNS. These data support a model in which PAK1 is a positive regulator of CNS myelination. Myelin is a critical component of the CNS that provides metabolic support to neurons and also facilitates communication between cells in the CNS. Recent data demonstrate that actin dynamics drives myelin wrapping, but how actin is regulated during myelin wrapping is unknown. The authors investigate the role of the cytoskeletal modulator PAK1 during differentiation and myelination by oligodendrocytes, the myelinating cells of the CNS. They demonstrate that PAK1 promotes oligodendrocyte differentiation and myelination by modulating the cytoskeleton and thereby internode length, thus playing a critical role in the function of the CNS.
细胞骨架对于少突胶质细胞分化和髓鞘形成至关重要。本文中，作者表明，作为一种众所周知的肌动蛋白调控因子，p21 激活激酶 1（PAK1）可促进中枢神经系统中少突胶质细胞的形态变化和髓鞘生成。结合 和 模型，作者证明 PAK1 在整个少突胶质细胞谱系中表达，在分化的少突胶质细胞中表达最高。在少突胶质细胞发育早期抑制 PAK1 会降低少突胶质细胞形态的复杂性，并改变少突胶质前体细胞突起末端的 F-肌动蛋白扩散。在雄性和雌性小鼠的少突胶质细胞中组成性激活 AKT，导致过度髓鞘包裹，增加 PAK1 的表达，这表明 PAK1 在活跃的髓鞘包裹过程中具有影响。此外，在斑马鱼的少突胶质细胞中组成性激活 PAK1 会导致髓鞘节段长度增加，而在活跃的髓鞘形成过程中抑制 PAK1 会导致髓鞘节段长度缩短。由于髓鞘参数会影响传导速度，这些数据表明 PAK1 可能会影响中枢神经系统内的通讯。这些数据支持 PAK1 是中枢神经系统髓鞘形成的正调控因子的模型。髓鞘是中枢神经系统的关键组成部分，为神经元提供代谢支持，并且有助于中枢神经系统中细胞间的通讯。最近的数据表明，肌动蛋白动力学驱动髓鞘包裹，但在髓鞘包裹过程中肌动蛋白如何被调控尚不清楚。作者研究了细胞骨架调节剂 PAK1 在少突胶质细胞分化和髓鞘形成中的作用，少突胶质细胞是中枢神经系统的髓鞘形成细胞。作者证明 PAK1 通过调节细胞骨架从而调节节段长度来促进少突胶质细胞的分化和髓鞘形成，因此在中枢神经系统的功能中发挥着关键作用。
