日本京都大学Ryoichiro Kageyama研究团队的最新成果表明，耦合延迟控制分节时钟的同步振荡。相关论文2020年1月8日在线发表于《自然》。
研究人员使用新型荧光报告基因（Achilles）建立了实时成像系统，通过将其与HES7融合在一起，以单细胞分辨率监测小鼠前体节中胚层（PSM）中HES7表达的同步振荡。野生型细胞可以快速纠正HES7振荡中的相位波动，而Notch调节基因Lfng（lunatic fringe）的缺失会导致PSM细胞之间失去同步。此外，在Lfng缺失PSM的各个单元中，HES7振荡会严重衰减。但是，当Lfng缺失PSM细胞完全解离时，HES7振荡的振幅和周期性几乎是正常的，这表明LFNG主要参与细胞间的耦合。对照和Lfng缺失PSM细胞的混合培养以及光遗传学Notch信号报告基因测定表明LFNG延迟了细胞间Notch信号传递的信号发送过程。这些结果与数学建模一起提高了Lfng缺失PSM单元缩短耦合延迟的可能性，从而达到了称为耦合振荡器的振荡或振幅消失的条件。实际上，延长耦合延迟的小化合物可以部分挽救Lfng缺失PSM细胞中HES7振荡的幅度和同步性。这项研究揭示了参与体节分割振荡网络的延迟控制机制，并表明具有正确延迟的细胞间偶联对于同步振荡至关重要。
研究人员表示，单个细胞的活动存在波动，但其通过细胞间的耦合在群体水平上不断协调。一个显著的例子是体节分割时钟，即时钟基因（例如Hes7）的表达在包括PSM的细胞之间发生同步振荡。这种同步取决于Notch信号通路。抑制该途径会使振荡失调，从而导致体节融合。但是，Notch信号如何调节HES7振荡的同步性尚不清楚。
附：英文原文
Title: Coupling delay controls synchronized oscillation in the segmentation clock
Author: Kumiko Yoshioka-Kobayashi, Marina Matsumiya, Yusuke Niino, Akihiro Isomura, Hiroshi Kori, Atsushi Miyawaki, Ryoichiro Kageyama
Issue&Volume: 2020-01-08
Abstract: Individual cellular activities fluctuate but are constantly coordinated at the population level via cellcell coupling. A notable example is the somite segmentation clock, in which the expression of clock genes (such as Hes7) oscillates in synchrony between the cells that comprise the presomitic mesoderm (PSM)1,2. This synchronization depends on the Notch signalling pathway; inhibiting this pathway desynchronizes oscillations, leading to somite fusion37. However, how Notch signalling regulates the synchronicity of HES7 oscillations is unknown. Here we establish a live-imaging system using a new fluorescent reporter (Achilles), which we fuse with HES7 to monitor synchronous oscillations in HES7 expression in the mouse PSM at a single-cell resolution. Wild-type cells can rapidly correct for phase fluctuations in HES7 oscillations, whereas the absence of the Notch modulator gene lunatic fringe (Lfng) leads to a loss of synchrony between PSM cells. Furthermore, HES7 oscillations are severely dampened in individual cells of Lfng-null PSM. However, when Lfng-null PSM cells were completely dissociated, the amplitude and periodicity of HES7 oscillations were almost normal, which suggests that LFNG is involved mostly in cellcell coupling. Mixed cultures of control and Lfng-null PSM cells, and an optogenetic Notch signalling reporter assay, revealed that LFNG delays the signal-sending process of intercellular Notch signalling transmission. These resultstogether with mathematical modellingraised the possibility that Lfng-null PSM cells shorten the coupling delay, thereby approaching a condition known as the oscillation or amplitude death of coupled oscillators8. Indeed, a small compound that lengthens the coupling delay partially rescues the amplitude and synchrony of HES7 oscillations in Lfng-null PSM cells. Our study reveals a delay control mechanism of the oscillatory networks involved in somite segmentation, and indicates that intercellular coupling with the correct delay is essential for synchronized oscillation. Monitoring cells of the mouse presomitic mesoderm using the Achilles reporter fused to HES7 sheds light on the mechanisms that underpin synchronous oscillations in the expression of clock genes between neighbouring cells.
DOI: 10.1038/s41586-019-1882-z
Source:https://www.nature.com/articles/s41586-019-1882-z
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
