Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of the Ministry of Education and the Collaborative Innovation Center for Brain Science, Second Military Medical University, Shanghai, 200433, China.
Department of Internal Medicine, Jiangsu Provincial Corps Hospital, Chinese People's Armed Police Force, Yangzhou, 225003, China.
Neurosci Bull. 2019 Oct;35(5):802-814. doi: 10.1007/s12264-019-00376-7. Epub 2019 Apr 26.
The correct differentiation of oligodendrocyte precursor cells (OPCs) is essential for the myelination and remyelination processes in the central nervous system. Determining the regulatory mechanism is fundamental to the treatment of demyelinating diseases. By analyzing the RNA sequencing data of different neural cells, we found that cyclin-dependent kinase 18 (CDK18) is exclusively expressed in oligodendrocytes. In vivo studies showed that the expression level of CDK18 gradually increased along with myelin formation during development and in the remyelination phase in a lysophosphatidylcholine-induced demyelination model, and was distinctively highly expressed in oligodendrocytes. In vitro overexpression and interference experiments revealed that CDK18 directly promotes the differentiation of OPCs, without affecting their proliferation or apoptosis. Mechanistically, CDK18 activated the RAS/mitogen-activated protein kinase kinase 1/extracellular signal-regulated kinase pathway, thus promoting OPC differentiation. The results of the present study suggest that CDK18 is a promising cell-type specific target to treat demyelinating disease.
少突胶质前体细胞（OPCs）的正确分化对于中枢神经系统的髓鞘形成和再髓鞘化过程至关重要。确定调控机制是治疗脱髓鞘疾病的基础。通过分析不同神经细胞的 RNA 测序数据，我们发现细胞周期蛋白依赖性激酶 18（CDK18）特异性表达于少突胶质细胞。体内研究表明，在发育过程中随着髓鞘形成，以及在溶血磷脂酰胆碱诱导的脱髓鞘模型的再髓鞘化阶段，CDK18 的表达水平逐渐升高，并且在少突胶质细胞中特异性高表达。体外过表达和干扰实验表明，CDK18 可直接促进 OPC 分化，而不影响其增殖或凋亡。机制上，CDK18 激活 RAS/丝裂原活化蛋白激酶激酶 1/细胞外信号调节激酶通路，从而促进 OPC 分化。本研究结果表明，CDK18 是治疗脱髓鞘疾病有前途的细胞类型特异性靶点。
