<br>c-Abl诱导的Olig2磷酸化调节少突胶质细胞前体细胞的增殖,Glia

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c-Abl诱导的Olig2磷酸化调节少突胶质细胞前体细胞的增殖
Glia ( IF 5.4 ) Pub Date : 2022-02-13 , DOI: 10.1002/glia.24157
Jun Zhang _{1,

2} , Jian-Guang Sun ₁ , Xiaowen Xing ₁ , Rong Wu ₁ , Lujun Zhou ₁ , Ying Zhang ₁ , Fang Yuan ₃ , Shukun Wang ₁ , Zengqiang Yuan _{1,

4}

Affiliation

少突胶质细胞 (OL) 是中枢神经系统 (CNS) 中的髓鞘形成细胞，由 OL 祖细胞 (OPC) 分化而来。现有 OPC 的增殖对于中枢神经系统发育过程中的髓鞘形成和响应脱髓鞘刺激的髓鞘再生是必不可少的。转录因子 Olig2 是 OL 规范所必需的，并在 OL 谱系中表达。然而，人们对 Olig2 在 OPC 增殖过程中的翻译后修饰知之甚少。在此，我们发现c-Abl主要在Tyr137位点直接磷酸化Olig2，并且Olig2磷酸化对于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 OPC 中高度表达。发育阶段OL特异性c-Abl敲除导致OPC增殖不足、髓磷脂相关基因表达减少和髓鞘形成迟缓。因此，c-Abl 特异性激酶抑制剂在体外抑制了 OPC 增殖。此外，我们观察到，在铜宗脱髓鞘模型中，OL 特异性 c-Abl 敲除减少了 OPC 增殖和髓鞘再生。此外，我们发现临床使用的c-Abl抑制剂尼洛替尼降低了小鼠髓鞘碱性蛋白（Mbp）的表达和运动协调能力，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 在疾病模型中发育髓鞘形成和髓鞘再生过程中 OL 中的重要作用。

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c-Abl-induced Olig2 phosphorylation regulates the proliferation of oligodendrocyte precursor cells

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.

更新日期：2022-02-13

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