Bhambri Aksheev, Thai Phu, Wei Songtao, Bae Han-Gyu, Barbosa Daniela, Sharma Tripti, Yu Ze, Xing Chao, Kim Jun Hee, Yu Guoqiang, Sun Lu O
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA 22203, USA.
bioRxiv. 2024 Dec 27:2024.12.27.630559. doi: 10.1101/2024.12.27.630559.
To myelinate axons, oligodendrocyte precursor cells (OPCs) must stop dividing and differentiate into premyelinating oligodendrocytes (preOLs). PreOLs are thought to survey and begin ensheathing nearby axons, and their maturation is often stalled at human demyelinating lesions. Lack of genetic tools to visualize and manipulate preOLs has left this critical differentiation stage woefully understudied. Here, we generated a knock-in mouse line that specifically labels preOLs across the central nervous system. Genetically labeled preOLs exhibit distinct morphology, unique transcriptomic and electrophysiological features, and do not overlap with OPCs. PreOL lineage tracing revealed that subsets of them undergo prolonged maturation and that different brain regions initiate oligodendrogenesis with the spatiotemporal specificity. Lastly, by fate mapping preOLs under sensory deprivation, we find that neuronal activity functions within a narrow time window of preOL maturation to promote their survival and successful integration. Our work provides a new tool to probe this critical cell stage during axon ensheathment, allowing for fine dissection of axon-oligodendrocyte interactions.
为了使轴突髓鞘化，少突胶质前体细胞（OPCs）必须停止分裂并分化为前髓鞘形成少突胶质细胞（preOLs）。人们认为preOLs会对附近的轴突进行监测并开始包裹它们，并且它们的成熟在人类脱髓鞘病变中常常停滞。缺乏用于可视化和操纵preOLs的遗传工具，使得这个关键的分化阶段的研究严重不足。在这里，我们生成了一种敲入小鼠品系，它能特异性地标记整个中枢神经系统中的preOLs。基因标记的preOLs表现出独特的形态、独特的转录组和电生理特征，并且与OPCs不重叠。preOL谱系追踪显示，其中一部分会经历长时间的成熟过程，并且不同的脑区以时空特异性的方式启动少突胶质细胞生成。最后，通过对感觉剥夺条件下的preOLs进行命运图谱分析，我们发现神经元活动在preOL成熟的狭窄时间窗口内发挥作用，以促进它们的存活和成功整合。我们的工作提供了一种新工具，用于探究轴突包裹过程中的这个关键细胞阶段，从而能够精细剖析轴突与少突胶质细胞之间的相互作用。
