Abstract：
In the central nervous system, the formation of myelin by oligodendrocytes (OLs) relies on the switch from the polymerization of the actin cytoskeleton to its depolymerization. The molecular mechanisms that trigger this switch have yet to be elucidated. Here, we identified P21-activated kinase 1 (PAK1) as a major regulator of actin depolymerization in OLs. Our results demonstrate that PAK1 accumulates in OLs in a kinase-inhibited form, triggering actin disassembly and, consequently, myelin membrane expansion. Remarkably, proteomic analysis of PAK1 binding partners enabled the identification of NF2/Merlin as its endogenous inhibitor. Our findings indicate that Nf2 knockdown in OLs results in PAK1 activation, actin polymerization, and a reduction in OL myelin membrane expansion. This effect is rescued by treatment with a PAK1 inhibitor. We also provide evidence that the specific Pak1 loss-of-function in oligodendroglia stimulates the thickening of myelin sheaths in vivo. Overall, our data indicate that the antagonistic actions of PAK1 and NF2/Merlin on the actin cytoskeleton of the OLs are critical for proper myelin formation. These findings have broad mechanistic and therapeutic implications in demyelinating diseases and neurodevelopmental disorders.
摘要：
在中枢神经系统中，少突胶质细胞(OLs)形成髓鞘依赖于肌动蛋白细胞骨架聚合向解聚的转变。触发这种开关的分子机制尚未阐明。这里,我们确定P21激活的激酶1（PAK1）是OLs中肌动蛋白解聚的主要调节因子。我们的结果表明，PAK1以激酶抑制的形式在OLs中积累，触发肌动蛋白拆卸和，因此,髓鞘膜扩张.值得注意的是,PAK1结合配偶体的蛋白质组学分析能够鉴定NF2/Merlin作为其内源性抑制剂。我们的发现表明，在OLs中Nf2敲低导致PAK1激活，肌动蛋白聚合，和髓磷脂膜扩张的减少。通过用PAK1抑制剂治疗来挽救这种效应。我们还提供证据表明，少突胶质细胞中特定的Pak1功能丧失会刺激体内髓鞘的增厚。总的来说,我们的数据表明，PAK1和NF2/Merlin对OL的肌动蛋白细胞骨架的拮抗作用对于正常的髓磷脂形成至关重要。这些发现在脱髓鞘疾病和神经发育障碍中具有广泛的机制和治疗意义。
