Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Beibei, Chongqing 400715, China.
Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, School of Basic Medicine, Chengdu Medical College, Xindu, Chengdu 610500, China.
Biomed Res Int. 2018 Jun 7;2018:6543196. doi: 10.1155/2018/6543196. eCollection 2018.
During somitogenesis, Fgf8 maintains the predifferentiation stage of presomitic mesoderm (PSM) cells and its retraction gives a cue for somite formation. Delta/Notch initiates the expression of oscillation genes in the tail bud and subsequently contributes to somite formation in a periodic way. Whether there exists a critical factor coordinating Fgf8 and Notch signaling pathways is largely unknown. Here, we demonstrate that the loss of function of geminin gave rise to narrower somites as a result of derepressed Fgf8 gradient in the PSM and tail bud. Furthermore, in geminin morphants, the somite boundary could not form properly but the oscillation of cyclic genes was normal, displaying the blurry somitic boundary and disturbed somite polarity along the AP axis. In mechanism, these manifestations were mediated by the disrupted association of the geminin/Brg1 complex with intron 3 of mib1. The latter interaction was found to positively regulate mib1 transcription, Notch activity, and sequential somite segmentation during somitogenesis. In addition, geminin was also shown to regulate the expression of deltaD in mib1-independent way. Collectively, our data for the first time demonstrate that geminin regulates Fgf8 and Notch signaling to regulate somite segmentation during somitogenesis.
在体节形成过程中，Fgf8 维持着体节前中胚层（PSM）细胞的预分化阶段，其回缩为体节形成提供了一个线索。Delta/Notch 在尾部芽中启动了振荡基因的表达，随后以周期性的方式促进体节形成。是否存在协调 Fgf8 和 Notch 信号通路的关键因素在很大程度上尚不清楚。在这里，我们证明了 geminin 的功能丧失导致 PSM 和尾部芽中 Fgf8 梯度去抑制，从而导致体节变窄。此外，在 geminin 形态发生缺陷体中，体节边界不能正常形成，但循环基因的振荡是正常的，表现为模糊的体节边界和沿 AP 轴的体节极性紊乱。在机制上，这些表现是由 geminin/Brg1 复合物与 mib1 内含子 3 的结合被破坏介导的。后者的相互作用被发现可正向调节 mib1 转录、Notch 活性和体节形成过程中的顺序体节分段。此外，geminin 还被证明以 mib1 非依赖性的方式调节 deltaD 的表达。总之，我们的数据首次表明 geminin 通过调节 Fgf8 和 Notch 信号通路来调节体节形成过程中的体节分段。
