Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada; Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada.
Cell Rep. 2019 Mar 19;26(12):3191-3202.e8. doi: 10.1016/j.celrep.2019.02.068.
Clock neurons within the mammalian suprachiasmatic nuclei (SCN) encode circadian time using interlocked transcription-translation feedback loops (TTFLs) that drive rhythmic gene expression. However, the contributions of other transcription factors outside of the circadian TTFLs to the functionality of the SCN remain obscure. Here, we report that the stem and progenitor cell transcription factor, sex-determining region Y-box 2 (SOX2), is expressed in adult SCN neurons and positively regulates transcription of the core clock gene, Period2. Mice lacking SOX2 selectively in SCN neurons display imprecise, poorly consolidated behavioral rhythms that do not entrain efficiently to environmental light cycles and that are highly susceptible to constant light-induced arrhythmicity. RNA sequencing revealed that Sox2 deficiency alters the SCN transcriptome, reducing the expression of core clock genes and neuropeptide-receptor systems. By defining the transcriptional landscape within SCN neurons, SOX2 enables the generation of robust, entrainable circadian rhythms that accurately reflect environmental time.
哺乳动物视交叉上核（SCN）中的时钟神经元使用互锁的转录-翻译反馈环（TTFL）来编码昼夜节律时间，从而驱动节律基因表达。然而，昼夜节律 TTFL 之外的其他转录因子对 SCN 功能的贡献仍然不清楚。在这里，我们报告性决定区 Y 框 2（SOX2），一种干细胞和祖细胞转录因子，在成年 SCN 神经元中表达，并正向调节核心时钟基因 Period2 的转录。在 SCN 神经元中特异性缺失 Sox2 的小鼠表现出不精确、整合不良的行为节律，不能有效地适应环境光周期，并且极易受到持续光照引起的节律失常的影响。RNA 测序显示 Sox2 缺失改变了 SCN 的转录组，降低了核心时钟基因和神经肽受体系统的表达。通过定义 SCN 神经元内的转录组图谱，SOX2 能够产生强大的、可适应的昼夜节律，准确反映环境时间。
