The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS.
The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS.
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DOI：
10.1038/cddis.2015.119
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发表时间：
2015-05-07
影响因子：
9
通讯作者：
Deng W
中科院分区：
文献类型：
--
作者：
Chung SH;Biswas S;Selvaraj V;Liu XB;Sohn J;Jiang P;Chen C;Chmilewsky F;Marzban H;Horiuchi M;Pleasure DE;Deng W
p38α丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）是一种丝氨酸/苏氨酸激酶，参与细胞的分化、迁移和分化等生物学过程。先前使用药理学抑制剂的体外研究表明，p38 MAPK对少突胶质细胞（OL）分化和髓鞘形成至关重要。为了研究p38α MAPK在体内OL发育和髓鞘形成中的特定作用，我们在PLP和神经/胶质抗原2（NG 2）基因启动子下产生p38α条件性敲除（CKO）小鼠，因为这些基因在OL祖细胞（OPCs）中特异性表达。我们的数据显示，在从NG 2 Cre-p38α CKO小鼠脑的原代OPC培养物分化的OL中，髓鞘合成被完全抑制。虽然在这些小鼠的大体检查后，在体内髓鞘形成缺陷是不明显的，电子显微镜分析表明，髓鞘束的超微结构严重受损。此外，与p38α fl/fl对照小鼠相比，敲除小鼠中胼胝体髓鞘形成的开始延迟。在中枢神经系统中观察到OL分化的延迟，伴随着OPC和OL特异性基因（如Olig 1和Zfp 488）在出生后早期发育过程中表达的下调。在此期间，OPC增殖不受影响。这些数据表明p38α是OL分化和髓鞘形成的正调节因子。出乎意料的是，我们观察到p38α在铜蛋白腙诱导的脱髓鞘模型中对髓鞘再生的相反作用。与p38α fl/fl小鼠相比，p38α CKO小鼠在脱髓鞘后表现出更好的髓鞘再生能力。p38α在髓鞘形成和髓鞘再生中的相反作用可能是由于p38α的强抗炎作用或p38α对发育过程中髓鞘形成和脱髓鞘后髓鞘再生的双重相互调节作用。
The p38α mitogen-activated protein kinase (MAPK) is one of the serine/threonine kinases regulating a variety of biological processes, including cell-type specification, differentiation and migration. Previous in vitro studies using pharmacological inhibitors suggested that p38 MAPK is essential for oligodendrocyte (OL) differentiation and myelination. To investigate the specific roles of p38α MAPK in OL development and myelination in vivo, we generated p38α conditional knockout (CKO) mice under the PLP and nerve/glial antigen 2 (NG2) gene promoters, as these genes are specifically expressed in OL progenitor cells (OPCs). Our data revealed that myelin synthesis was completely inhibited in OLs differentiated from primary OPC cultures derived from the NG2 Cre-p38α CKO mouse brains. Although an in vivo myelination defect was not obvious after gross examination of these mice, electron microscopic analysis showed that the ultrastructure of myelin bundles was severely impaired. Moreover, the onset of myelination in the corpus callosum was delayed in the knockout mice compared with p38α fl/fl control mice. A delay in OL differentiation in the central nervous system was observed with concomitant downregulation in the expression of OPC- and OL-specific genes such as Olig1 and Zfp488 during early postnatal development. OPC proliferation was not affected during this time. These data indicate that p38α is a positive regulator of OL differentiation and myelination. Unexpectedly, we observed an opposite effect of p38α on remyelination in the cuprizone-induced demyelination model. The p38α CKO mice exhibited better remyelination capability compared with p38α fl/fl mice following demyelination. The opposing roles of p38α in myelination and remyelination could be due to a strong anti-inflammatory effect of p38α or a dual reciprocal regulatory action of p38α on myelin formation during development and on remyelination after demyelination.