Transcription factor 7-like 2 (TCF7l2) regulates CNS myelination separating from its role in upstream oligodendrocyte differentiation.

IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Neurochemistry Pub Date : 2024-08-20 DOI:10.1111/jnc.16208
Sheng Zhang, Meina Zhu, Zhaohui Lan, Fuzheng Guo
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Abstract

Oligodendrocyte progenitor cells (OPCs) differentiation into oligodendrocytes (OLs) and subsequent myelination are two closely coordinated yet differentially regulated steps for myelin formation and repair in the CNS. Previously thought as an inhibitory factor by activating Wnt/beta-catenin signaling, we and others have demonstrated that the Transcription factor 7-like 2 (TCF7l2) promotes OL differentiation independent of Wnt/beta-catenin signaling activation. However, it remains elusive if TCF7l2 directly controls CNS myelination separating from its role in upstream oligodendrocyte differentiation. This is partially because of the lack of genetic animal models that could tease out CNS myelination from upstream OL differentiation. Here, we report that constitutively depleting TCF7l2 transiently inhibited oligodendrocyte differentiation during early postnatal development, but it impaired CNS myelination in the long term in adult mice. Using time-conditional and developmental-stage-specific genetic approaches, we further showed that depleting TCF7l2 in already differentiated OLs did not impact myelin protein gene expression nor oligodendroglial populations, instead, it perturbed CNS myelination in the adult. Therefore, our data convincingly demonstrate the crucial role of TCF7l2 in regulating CNS myelination independent of its role in upstream oligodendrocyte differentiation.

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转录因子 7-like 2(TCF7l2)调节中枢神经系统髓鞘化的作用与其在上游少突胶质细胞分化中的作用相分离。
少突胶质祖细胞(OPCs)分化成少突胶质细胞(OLs)以及随后的髓鞘化是中枢神经系统中髓鞘形成和修复的两个密切配合但又受不同调控的步骤。我们和其他人已经证明,转录因子 7-like 2(TCF7l2)能促进少突胶质细胞的分化,而不依赖于 Wnt/beta-catenin 信号的激活。然而,除了在上游少突胶质细胞分化中的作用外,TCF7l2 是否能直接控制中枢神经系统的髓鞘化仍是一个未知数。部分原因是缺乏能将中枢神经系统髓鞘化与上游少突胶质细胞分化区分开来的遗传动物模型。在这里,我们报告了组成性消耗 TCF7l2 在小鼠出生后早期发育过程中短暂抑制少突胶质细胞分化,但在成年小鼠中却长期损害中枢神经系统的髓鞘化。通过使用时间条件和发育阶段特异性遗传方法,我们进一步发现,在已经分化的少突胶质细胞中消耗 TCF7l2 不会影响髓鞘蛋白基因的表达或少突胶质细胞的数量,相反,它会扰乱成年小鼠的中枢神经系统髓鞘化。因此,我们的数据令人信服地证明了 TCF7l2 在调节中枢神经系统髓鞘化过程中的关键作用,而非其在上游少突胶质细胞分化过程中的作用。
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来源期刊
Journal of Neurochemistry
Journal of Neurochemistry 医学-神经科学
CiteScore
9.30
自引率
2.10%
发文量
181
审稿时长
2.2 months
期刊介绍: Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.
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