Zhejiang Key Laboratory of Organ Development and Regeneration, Institute of Life Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China.
Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, Kentucky.
Glia. 2020 Feb;68(2):422-434. doi: 10.1002/glia.23729. Epub 2019 Oct 12.
Elucidation of signaling pathways that control oligodendrocyte (OL) development is a prerequisite for developing novel strategies for myelin repair in neurological diseases. Despite the extensive work outlining the importance of Hedgehog (Hh) signaling in the commitment and generation of OL progenitor cells (OPCs), there are conflicting reports on the role of Hh signaling in regulating OL differentiation and maturation. In the present study, we systematically investigated OPC specification and differentiation in genetically modified mouse models of Smoothened (Smo), an essential component of the Hh signaling pathway in vertebrates. Through conditional gain-of-function strategy, we demonstrated that hyperactivation of Smo in neural progenitors induced transient ectopic OPC generation and precocious OL differentiation accompanied by the co-induction of Olig2 and Nkx2.2. After the commitment of OL lineage, Smo activity is not required for OL differentiation, and sustained expression of Smo in OPCs stimulated cell proliferation but inhibited terminal differentiation. These findings have uncovered the stage-specific regulation of OL development by Smo-mediated Hh signaling, providing novel insights into the molecular regulation of OL differentiation and myelin repair.
阐明调控少突胶质细胞（OL）发育的信号通路是开发神经系统疾病髓鞘修复新策略的前提。尽管有大量工作强调了 Hedgehog（Hh）信号在 OL 祖细胞（OPC）的分化和产生中的重要性，但关于 Hh 信号在调控 OL 分化和成熟中的作用仍存在矛盾的报道。在本研究中，我们通过遗传修饰小鼠模型系统地研究了 Smoothened（Smo），即脊椎动物 Hh 信号通路的一个重要组成部分，对 OPC 特化和分化的影响。通过条件性功能获得策略，我们证实了神经祖细胞中 Smo 的过度激活诱导了短暂的异位 OPC 产生和 OL 分化的提前，同时伴随着 Olig2 和 Nkx2.2 的共诱导。在 OL 谱系的分化后，Smo 活性不再是 OL 分化所必需的，而在 OPC 中持续表达 Smo 会刺激细胞增殖，但抑制终末分化。这些发现揭示了 Smo 介导的 Hh 信号对 OL 发育的阶段特异性调控，为 OL 分化和髓鞘修复的分子调控提供了新的见解。
