Demyelination Regulates the Circadian Transcription Factor BMAL1 to Signal Adult Neural Stem Cells to Initiate Oligodendrogenesis
Demyelination Regulates the Circadian Transcription Factor BMAL1 to Signal Adult Neural Stem Cells to Initiate Oligodendrogenesis
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DOI：
10.1016/j.celrep.2020.108394
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发表时间：
2020-11-17
期刊：
影响因子：
8.8
通讯作者：
Kim, Jin Young
中科院分区：
文献类型：
--
作者：
Huang, Suihong;Choi, Ming Ho;Kim, Jin Young
生物钟是内源性振荡器，产生控制细胞过程的细胞自主节律，并由局部宏观和微观环境中的外部信号同步。脱髓鞘是一种常见的脑病理，具有不同程度的恢复，通过受损的髓鞘和神经胶质细胞的激活改变微环境。这些微环境变化是如何影响当地生物钟的，以及会产生什么后果，目前大多尚不清楚。在这里，我们发现在脱髓鞘病变中，星形细胞生物钟产生Wnt抑制剂SFRP1和SFRP5。出乎意料的是，SFRP1和SFRP5向室下区（SVZ）发出信号，以降低昼夜节律转录因子BMAL1。这一系列事件导致SVZ中的成体神经干细胞分化为少突胶质细胞系细胞，然后将其提供给脱髓鞘病变。我们的研究结果表明，脱髓鞘病变中的生物钟对微环境变化做出反应，并与SVZ沟通，以增强自发髓鞘再生的自然修复系统。
Circadian clocks are endogenous oscillators that generate cell-autonomous rhythms that govern cellular processes and are synchronized by external cues in the local macro- and micro-environments. Demyelination, a common brain pathology with variable degrees of recovery, changes the microenvironment via damaged myelin and activation of glial cells. How these microenvironmental changes affect local circadian clocks and with what consequences is mostly unknown. Here, we show that within demyelinating lesions, astrocyte circadian clocks produce the Wnt inhibitors SFRP1 and SFRP5. Unexpectedly, SFRP1 and SFRP5 signal to the subventricular zone (SVZ) to reduce the circadian transcription factor BMAL1. This sequence of events causes adult neural stem cells in the SVZ to differentiate into oligodendrocyte lineage cells, which are then supplied to demyelinated lesions. Our findings show that circadian clocks in demyelinating lesions respond to microenvironmental changes and communicate with the SVZ to enhance a natural repair system of spontaneous remyelination.