c‐Abl‐induced Olig2 phosphorylation regulates the proliferation of oligodendrocyte precursor cells
c‐Abl‐induced Olig2 phosphorylation regulates the proliferation of oligodendrocyte precursor cells
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DOI：
10.1002/glia.24157
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发表时间：
2022-02
期刊：
影响因子：
6.2
通讯作者：
Jun Zhang;Jian-guang Sun;Xiaowen Xing;R. Wu;Lujun Zhou;Ying Zhang;Fang Yuan;Shukun Wang;Zengqiang Yuan
中科院分区：
文献类型：
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作者：
Jun Zhang;Jian-guang Sun;Xiaowen Xing;R. Wu;Lujun Zhou;Ying Zhang;Fang Yuan;Shukun Wang;Zengqiang Yuan
少突胶质细胞（OLs）是中枢神经系统（CNS）中的髓鞘细胞，由OL祖细胞（OPCs）分化而来。现有OPCs的增殖对于中枢神经系统发育过程中的髓鞘形成和脱髓鞘刺激下的再髓鞘形成是必不可少的。转录因子Olig2是OL的规范所必需的，并在OL谱系中表达。然而，Olig2在OPCs增殖中的翻译后修饰尚不清楚。在此，我们发现c‐Abl主要在Tyr137位点直接磷酸化Olig2，并且Olig2磷酸化对OPC增殖至关重要。随着大脑发育，c - Abl的表达水平逐渐降低；此外，c‐Abl在OPCs中高表达。在发育阶段敲除OL特异性c - Abl可导致OPCs增殖不足、髓磷脂相关基因表达减少和髓鞘发育迟缓。因此，c - Abl特异性激酶抑制剂可抑制OPC体外增殖。此外，我们观察到OL特异性c - Abl敲除可以减少OPC增殖和脱髓鞘cuprizone模型中的再髓鞘形成。此外，我们发现临床使用的c - Abl抑制剂尼罗替尼降低了小鼠髓鞘碱性蛋白（Mbp）的表达和运动协调性，表明长期服用c - Abl抑制剂会产生神经系统副作用。因此，我们确定了c - Abl在疾病模型中发育性髓鞘形成和再髓鞘形成过程中的OLs中的重要作用。
Oligodendrocytes (OLs), the myelinating cells in the central nervous system (CNS), are differentiated from OL progenitor cells (OPCs). The proliferation of existing OPCs is indispensable for myelination during CNS development and remyelination in response to demyelination stimulation. The transcription factor Olig2 is required for the specification of OLs and is expressed in the OL lineage. However, the post‐translational modification of Olig2 in the proliferation of OPCs is poorly understood. Herein, we identified that c‐Abl directly phosphorylates Olig2 mainly at the Tyr137 site, and that Olig2 phosphorylation is essential for OPC proliferation. The expression levels of c‐Abl gradually decreased with brain development; moreover, c‐Abl was highly expressed in OPCs. OL‐specific c‐Abl knockout at the developmental stage led to an insufficient proliferation of OPCs, a decreased expression of myelin‐related genes, and myelination retardation. Accordingly, a c‐Abl‐specific kinase inhibitor suppressed OPC proliferation in vitro. Furthermore, we observed that OL‐specific c‐Abl knockout reduced OPC proliferation and remyelination in a cuprizone model of demyelination. In addition, we found that nilotinib, a clinically used c‐Abl inhibitor, decreased the expression of myelin basic protein (Mbp) and motor coordination in mice, indicating a neurological side effect of a long‐term administration of the c‐Abl inhibitor. Thus, we identified the important role of c‐Abl in OLs during developmental myelination and remyelination in a disease model.