脊椎动物体节形成的分节时钟调控机制  

Segmentation Clock Networks in Vertebrate Somitogenesis

作　　者：孙青 王宇[3] 阿尖措[4] 郝岩 李岩 SUN Qing;WANG Yu;CUO-A Jian;HAO Yan;LI Yan(College of Life Sciences,University of Chinese Academy of Sciences,Beijing 100049,China;Key Laboratory of Epigenetic Regulation and Intervention,Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China;Peking University First Hospital,Beijing 100035,China;Qinghai Red Cross Hospital,Xining 810099,China)

机构地区：[1]中国科学院大学生命科学学院,北京100049 [2]中国科学院生物物理研究所表观遗传调控与干预重点实验室,北京100101 [3]北京大学第一医院,北京100035 [4]青海红十字医院,西宁810099

出　　处：《生物化学与生物物理进展》2024年第4期731-742,共12页Progress In Biochemistry and Biophysics

基　　金：青海省应用基础研究计划(2021-ZJ-746);智善基金(Huanghong&Lili Project 2022);中国科学院战略性先导科技专项(XDB38010200)资助项目。

摘　　要：脊椎动物胚胎发育早期中胚层细胞的分节时钟控制着体节的周期性形成。体节是沿身体轴的重复结构,最终发育形成椎骨和肋骨。如果分节时钟受到干扰,体节形成就会出现缺陷,从而导致身体发育异常,最终产生脊柱先天性疾病。参与体节发育的主要模型是时钟和波前模型。中胚层分化由组合梯度系统调节,该系统涉及成纤维细胞生长因子(FGF)、Wnt/β-catenin和视黄酸(RA)信号通路。FGF信号和Wnt/β-catenin信号控制后中胚层处于未分化状态,RA信号则诱导前中胚层细胞分化导致体节成熟。因此相反的信号梯度在特定位点达到平衡。当分子振荡器从尾芽起始表达并以行波模式向前传播至信号平衡临界点时,将启动分节时钟程序,触发Mesp2等分化基因表达,表现为未成熟的前体节中胚层发育形成一对体节。随着细胞二维培养体系和时事报告系统的成熟,研究人员成功在体外将干细胞诱导分化至中胚层并实现了分节时钟的二维可视化振荡。研究表明,细胞通信中的耦合延迟可以保持相邻细胞之间同步振荡,因此导致体节边界和双侧对称形成。此后研究人员在体外重建了诱导多能干细胞的三维培养系统,再现了具有前-后(AP)轴特征的体节样结构的形成。这为解码分节时钟网络调控机理、探索体节双侧对称形成以及不同物种发育速率的代谢调控机制提供了一个宝贵的研究体系。同时为探索病理性体节缺陷发展中的失调机制创造了一个平台。In vertebrate embryonic development,the segmentation clock controls the cyclic formation of somites through presomitic mesoderm(PSM)cells.Somites are paired segmented structures along the anterior-posterior axis that eventually develop into vertebrae and ribs.Disruptions in the segmentation clock leads to defects in somitogenesis,resulting in congenital spinal diseases.The major patterning modules that are involved in segmentation clock is the clock and wavefront,which primarily relies on signaling gradients and cyclic oscillation.Mesodermal differentiation is regulated by combinatorial gradient system that involves the activity of the fibroblast growth factor(FGF),the Wnt/β-catenin,and the retinoic acid(RA)signaling pathways.The antagonistic gradients of these signals set a position of the determination front.In the tail bud and posterior mesoderm,FGF and Wnt signaling prevent cell maturation and the molecular oscillators start to express.The molecular oscillators rely on negative feedback loops to maintain their oscillatory expression patterns.As the cells move anteriorly,FGF signaling gradually decays and RA signaling began to strengthen.Meanwhile,the molecular oscillators propagate anteriorly with wave pattern.At the determination front,low levels of FGF signaling and high levels of RA signaling eliminate differentiation inhibition and initiate molecular oscillators to activate cyclic genes,such as Mesp2,leading to the formation of repetitive structures in somites.Advancements in live reporter and 2D culture systems have revealed that coupling delays in cell communication can maintain the synchronous segmentation clock between adjacent cells.Studies have shown that these coupling delays are controlled by Lfng gene,it can adjust coupling delays to fit in-phase oscillations by increasing the time required for intercellular DLL1-Notch signaling.To sum up,the dual homeostasis of opposing signaling gradients determines the segment boundaries,the distance traveled by a molecular oscillator in one oscillation cycle

关 键 词：分节时钟 体节形成 信号梯度 周期振荡 同步振荡 

分 类 号：Q2[生物学—细胞生物学] Q7