Ddx20, DEAD box helicase 20, is essential for the differentiation of oligodendrocyte and maintenance of myelin gene expression
Ddx20, DEAD box helicase 20, is essential for the differentiation of oligodendrocyte and maintenance of myelin gene expression
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DOI：
10.1002/glia.24058
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发表时间：
2021-07-07
期刊：
影响因子：
6.2
通讯作者：
Takebayashi, Hirohide
中科院分区：
文献类型：
--
作者：
Simankova, Anna;Bizen, Norihisa;Takebayashi, Hirohide
少突胶质细胞形成围绕轴突的髓鞘，有助于跳跃式传导和中枢神经系统的正常功能。少突胶质细胞祖细胞（OPCs）在胚胎阶段产生，并在出生后分化为髓鞘少突胶质细胞。Ddx20是一种多功能的DEAD-box解旋酶，参与多种细胞过程，包括转录、剪接、microRNA生物发生和翻译。虽然这些过程中的缺陷都会导致少突胶质细胞分化和髓鞘形成异常，但Ddx20在少突胶质细胞末梢分化中的作用尚不清楚。为了解决这个问题，我们使用Mbp-Cre小鼠产生Ddx20条件敲除（cKO）小鼠，以允许从成熟少突胶质细胞中删除Ddx20。Mbp-Cre;Ddx20 cKO小鼠表现出体型小、行为异常、肌肉无力和寿命短，在2个月大时死亡。组织学分析显示，在出生后42天，成熟少突胶质细胞的数量显著减少，髓磷脂相关mrna（如Mbp和Plp）的表达水平急剧下降。opc的数量没有变化。电镜观察发现，Ddx20 cKO小鼠大直径轴突有薄髓鞘层。溴脱氧尿苷（BrdU）标记实验表明，Mbp-Cre的中枢神经系统终末分化在2 ~ 7周龄受到干扰；Ddx20 cKO小鼠。免疫组织化学检测显示，Ddx20 cKO小鼠中促进髓鞘形成的丝裂原活化蛋白（MAP）激酶的激活下调。这些结果表明，Ddx20是少突胶质细胞终末分化和髓磷脂基因表达维持的重要因子。
Oligodendrocytes form myelin sheaths that surround axons, contributing to saltatory conduction and proper central nervous system (CNS) function. Oligodendrocyte progenitor cells (OPCs) are generated during the embryonic stage and differentiate into myelinating oligodendrocytes postnatally. Ddx20 is a multifunctional, DEAD-box helicase involved in multiple cellular processes, including transcription, splicing, microRNA biogenesis, and translation. Although defects in each of these processes result in abnormal oligodendrocyte differentiation and myelination, the involvement of Ddx20 in oligodendrocyte terminal differentiation remains unknown. To address this question, we used Mbp-Cre mice to generate Ddx20 conditional knockout (cKO) mice to allow for the deletion of Ddx20 from mature oligodendrocytes. Mbp-Cre;Ddx20 cKO mice demonstrated small body sizes, behavioral abnormalities, muscle weakness, and short lifespans, with mortality by the age of 2 months old. Histological analyses demonstrated significant reductions in the number of mature oligodendrocytes and drastic reductions in the expression levels of myelin-associated mRNAs, such as Mbp and Plp at postnatal day 42. The number of OPCs did not change. A thin myelin layer was observed for large-diameter axons in Ddx20 cKO mice, based on electron microscopic analysis. A bromodeoxyuridine (BrdU) labeling experiment demonstrated that terminal differentiation was perturbed from ages 2 weeks to 7 weeks in the CNS of Mbp-Cre;Ddx20 cKO mice. The activation of mitogen-activated protein (MAP) kinase, which promotes myelination, was downregulated in the Ddx20 cKO mice based on immunohistochemical detection. These results indicate that Ddx20 is an essential factor for terminal differentiation of oligodendrocytes and maintenance of myelin gene expression.