Kageyama Ryoichiro, Niwa Yasutaka, Isomura Akihiro, González Aitor, Harima Yukiko
Institute for Virus Research, Kyoto University, Kyoto, Japan.
Wiley Interdiscip Rev Dev Biol. 2012 Sep-Oct;1(5):629-41. doi: 10.1002/wdev.46. Epub 2012 Mar 22.
A bilateral pair of somites forms periodically by segmentation of the anterior ends of the presomitic mesoderm (PSM). This periodic event is regulated by a biological clock called the segmentation clock, which involves cyclic gene expression. Expression of her1 and her7 in zebrafish and Hes7 in mice oscillates by negative feedback, and mathematical models have been used to generate and test hypotheses to aide elucidation of the role of negative feedback in regulating oscillatory expression. her/Hes genes induce oscillatory expression of the Notch ligand deltaC in zebrafish and the Notch modulator Lunatic fringe in mice, which lead to synchronization of oscillatory gene expression between neighboring PSM cells. In the mouse PSM, Hes7 induces coupled oscillations of Notch and Fgf signaling, while Notch and Fgf signaling cooperatively regulate Hes7 oscillation, indicating that Hes7 and Notch and Fgf signaling form the oscillator networks. Notch signaling activates, but Fgf signaling represses, expression of the master regulator for somitogenesis Mesp2, and coupled oscillations in Notch and Fgf signaling dissociate in the anterior PSM, which allows Notch signaling-induced synchronized cells to express Mesp2 after these cells are freed from Fgf signaling. These results together suggest that Notch signaling defines the prospective somite region, while Fgf signaling regulates the pace of segmentation. It is likely that these oscillator networks constitute the core of the segmentation clock, but it remains to be determined whether as yet unknown oscillators function behind the scenes.
一对双侧体节通过分割前体节中胚层（PSM）的前端周期性地形成。这一周期性事件受一种称为分割时钟的生物钟调节，该生物钟涉及周期性基因表达。斑马鱼中her1和her7以及小鼠中Hes7的表达通过负反馈振荡，并且数学模型已被用于生成和测试假设，以帮助阐明负反馈在调节振荡表达中的作用。her/Hes基因诱导斑马鱼中Notch配体deltaC以及小鼠中Notch调节剂Lunatic fringe的振荡表达，这导致相邻PSM细胞之间振荡基因表达的同步。在小鼠PSM中，Hes7诱导Notch和Fgf信号的耦合振荡，而Notch和Fgf信号协同调节Hes7振荡，表明Hes7与Notch和Fgf信号形成了振荡器网络。Notch信号激活体节发生主调节因子Mesp2的表达，但Fgf信号抑制其表达，并且Notch和Fgf信号的耦合振荡在前部PSM中解离，这使得Notch信号诱导的同步细胞在摆脱Fgf信号后能够表达Mesp2。这些结果共同表明，Notch信号定义了预期的体节区域，而Fgf信号调节分割的速度。这些振荡器网络很可能构成了分割时钟的核心，但幕后是否还有未知的振荡器发挥作用仍有待确定。
