Zou Yanping, Jin Yili, Yang Yuqian, Zhang Liuning, Feng Yuanyu, Long Yu, Xu ZhengTao, He Yuehua, Zheng Wei, Wang Shuming, He Yongxiang, Li Jiong, Li Huiliang, Luo Zhigang, Hu Chun, Xiao Lin
Key Laboratory of Brain, Cognition and Education Sciences of Ministry of Education; Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, and Center for Studies of Psychological Application, South China Normal University, Guangzhou, China.
Wolfson Institute for Biomedical Research, University College London, London, UK.
Glia. 2025 Apr;73(4):840-856. doi: 10.1002/glia.24658. Epub 2025 Jan 1.
Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system (CNS), develop from OL precursor cells (OPCs) through a complex process involving significant morphological changes that are critically dependent on the dynamic interactions between cytoskeletal networks. Growth arrest-specific 2-like protein 1 (GAS2L1) is a cytoskeletal linker protein that mediates the cross-talk between actin filaments and microtubules. However, its role in OL and myelin development remains unknown. Here, we report that GAS2L1 is expressed in both OPCs and mature OLs, and that overexpression or knockdown of Gas2l1 in cultured OPCs in vitro impaired or enhanced their differentiation, respectively, while both inhibited their proliferation. We generated a Gas2l1 mouse line and found that mice with conditional knockout of Gas2l1 in OL lineage cells (Olig1-Cre;Gas2l1 , cKO) showed an increased number of mature OLs and enhanced myelination, as well as a reduction in the branching complexity of OPCs. In addition, an alternative mouse line with postnatally induced Gas2l1 ablation specifically in OPCs (Pdfgra-CreER ;Gas2l1 , iKO) recapitulated the acceleration of OL and myelin development as well as the inhibition of OPC process branching. Furthermore, EdU tracking in Gas2l1 iKO mice in vivo and in their OPC cultures in vitro showed both a reduction in OPC proliferation and an increase in OL maturation. Finally, cultured OPCs from iKO mice showed an increase in filopodia extension. Taken together, our results demonstrate an effect of GAS2L1 on the regulation of OL/myelin development and may provide a novel potential therapeutic target for various diseases involving OL/myelin pathology.
少突胶质细胞（OLs）是中枢神经系统（CNS）中形成髓鞘的细胞，它们从少突胶质前体细胞（OPCs）发育而来，这一过程复杂，涉及显著的形态变化，而这些变化严重依赖于细胞骨架网络之间的动态相互作用。生长停滞特异性2样蛋白1（GAS2L1）是一种细胞骨架连接蛋白，介导肌动蛋白丝和微管之间的相互作用。然而，其在OLs和髓鞘发育中的作用尚不清楚。在此，我们报告GAS2L1在OPCs和成熟OLs中均有表达，在体外培养的OPCs中过表达或敲低Gas2l1分别损害或增强了它们的分化，同时两者均抑制了它们的增殖。我们构建了一个Gas2l1小鼠品系，发现OL谱系细胞中条件性敲除Gas2l1的小鼠（Olig1-Cre;Gas2l1 ，cKO）显示成熟OLs数量增加、髓鞘形成增强，以及OPCs分支复杂性降低。此外，另一个在出生后特异性诱导OPCs中Gas2l1缺失的小鼠品系（Pdfgra-CreER ;Gas2l1 ，iKO）重现了OL和髓鞘发育的加速以及OPC突起分支的抑制。此外，对Gas2l1 iKO小鼠进行体内EdU追踪以及对其体外OPC培养物进行追踪，结果均显示OPC增殖减少以及OL成熟增加。最后，来自iKO小鼠的体外培养OPCs显示丝状伪足延伸增加。综上所述，我们的结果证明了GAS2L1对OL/髓鞘发育调节的作用，并可能为涉及OL/髓鞘病理的各种疾病提供一个新的潜在治疗靶点。
