C1ql1 expression in oligodendrocyte progenitor cells promotes oligodendrocyte differentiation

Zeynep M. Altunay, Joyshree Biswas, Hiu W. Cheung, Robert S. Pijewski, Lucille E. Papile, Yetunde O. Akinlaja, Andrew Tang, Lyndsay C. Kresic, Alexander D. Schouw, Maksym V. Ugrak, Keaven Caro, Perla A. Peña Palomino, Susanne Ressl, Akiko Nishiyama, Stephen J. Crocker, David C. Martinelli
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Abstract

Myelinating oligodendrocytes arise from the stepwise differentiation of oligodendrocyte progenitor cells (OPCs). Approximately 5% of all adult brain cells are OPCs. Why would a mature brain need such a large number of OPCs? New myelination is possibly required for higher‐order functions such as cognition and learning. Additionally, this pool of OPCs represents a source of new oligodendrocytes to replace those lost during injury, inflammation, or in diseases such as multiple sclerosis (MS). How OPCs are instructed to differentiate into oligodendrocytes is poorly understood, and for reasons presently unclear, resident pools of OPCs are progressively less utilized in MS. The complement component 1, q subcomponent‐like (C1QL) protein family has been studied for their functions at neuron–neuron synapses, but we show that OPCs express C1ql1. We created OPC‐specific conditional knockout mice and show that C1QL1 deficiency reduces the differentiation of OPCs into oligodendrocytes and reduces myelin production during both development and recovery from cuprizone‐induced demyelination. In vivo over‐expression of C1QL1 causes the opposite phenotype: increased oligodendrocyte density and myelination during recovery from demyelination. We further used primary cultured OPCs to show that C1QL1 levels can bidirectionally regulate the extent of OPC differentiation in vitro. Our results suggest that C1QL1 may initiate a previously unrecognized signaling pathway to promote differentiation of OPCs into oligodendrocytes. This study has relevance for possible novel therapies for demyelinating diseases and may illuminate a previously undescribed mechanism to regulate the function of myelination in cognition and learning.
少突胶质祖细胞中 C1ql1 的表达可促进少突胶质细胞的分化
髓鞘化少突胶质细胞由少突胶质祖细胞(OPC)逐步分化而来。成人脑细胞中约有 5% 是 OPCs。为什么成熟的大脑需要如此大量的 OPCs?认知和学习等高阶功能可能需要新的髓鞘化。此外,这个 OPCs 库也是新的少突胶质细胞的来源,可以替代在损伤、炎症或多发性硬化症(MS)等疾病中丢失的少突胶质细胞。人们对 OPCs 如何分化成少突胶质细胞还知之甚少,而且由于目前尚不清楚的原因,OPCs 常驻池在多发性硬化症中的利用率逐渐降低。补体成分 1 q 亚组分样蛋白(C1QL)家族因其在神经元-神经元突触处的功能而受到研究,但我们发现 OPCs 也表达 C1ql1。我们创建了 OPC 特异性条件性基因敲除小鼠,结果表明 C1QL1 缺乏会减少 OPCs 向少突胶质细胞的分化,并在发育和铜绿素诱导的脱髓鞘恢复过程中减少髓鞘的生成。在体内过量表达 C1QL1 则会导致相反的表型:在脱髓鞘恢复期间,少突胶质细胞密度和髓鞘化增加。我们进一步使用原代培养的OPCs表明,C1QL1水平可双向调节体外OPC分化的程度。我们的研究结果表明,C1QL1可能启动了一条之前尚未认识到的信号通路,促进OPC向少突胶质细胞分化。这项研究对脱髓鞘疾病可能的新型疗法具有重要意义,并可能揭示出一种以前未曾描述过的机制,以调节髓鞘在认知和学习中的功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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