Molecular Analysis of the Segmentation Clock

描述（由申请人提供）：我们对脊椎动物轴的形态发生感兴趣，更具体地说，对身体的同色异谱结构的模式化和分化感兴趣。在脊椎动物胚胎中，最明显的同色异谱结构是体节，体节产生身体的分段结构，包括中轴骨骼、背部真皮和所有骨骼肌。与该应用相关的研究的中心主题是了解级联事件，其在分子水平上调节脊椎动物胚胎的身体计划的分割。我们将主要集中在一个分子振荡器的研究称为“分段时钟”，我们确定了几年前。这种分子钟的节奏与分割的节奏平行，最初是在鸡胚胎中发现的，作为编码前体中胚层（PSM）中特定基因的mRNA的脉冲。分段时钟现在已经在鱼、鸡和小鼠中被确定，并且控制“循环基因”的周期性表达，到目前为止，这些基因都与Notch途径有关。目前，无论是分割时钟的机制，还是它在分割过程中的确切作用，都还不清楚。 关于分段时钟的分子机制的一个主要问题是Notch信号的作用。我们在小鼠和鱼类中的初步研究和遗传证据表明，该途径在控制振荡中起着重要作用，但尚不清楚它是否在振荡器的核心机制中起作用。该项目的一个主要目标是在分子和细胞水平上进行实验，以表征Notch途径在振荡器功能中的作用。我们还发现，FGF信号控制激活的分割程序和定位的体节边界在鸡胚。我们打算建立在这个过程中的FGF途径的各种组件的含义，我们将检查FGF信号与分割时钟的相互作用。最后，我们提供了证据之间的耦合分割时钟和激活或维护的Hox基因在轴的形成，我们打算进一步表征这种相互作用在鸡胚胎发生。 对分段时钟的功能的理解具有相当大的临床意义，因为在人类中，与该振荡器的功能相关的基因中的突变（例如δ样3（dll3））导致脊柱的异常分段，类似于在脊椎肋骨发育不全综合征中所看到的。

DESCRIPTION (provided by applicant): We are interested in the morphogenesis of the vertebrate axis and more particularly in the patterning and differentiation of the metameric structures of the body. In the vertebrate embryo, the most overt metameric structures are the somites, which give rise to the segmented structures of the body including the axial skeleton, the dermis of the back and all skeletal muscles. The central theme of the research relevant to this application is to understand the cascade of events, which regulate the segmentation of the body plan of vertebrate embryos at the molecular level. We will essentially focus on the study of a molecular oscillator called the " Segmentation Clock" which we identified a few years ago. This molecular clock whose rhythm parallels that of segmentation was originally discovered in the chick embryo as pulses of mRNA coding for specific genes in the presomitic mesoderm (PSM). The Segmentation Clock has now been identified in fish, chick and mouse and controls the periodic expression of "Cyclic Genes " which are, so far, all related to the Notch pathway. Neither the mechanism underlying the Segmentation Clock nor its precise role in the segmentation process are currently understood. A major question to be asked regarding the molecular machinery of the Segmentation Clock concerns the role of Notch signaling. Our preliminary studies and genetic evidence in mouse and fish suggest that this pathway plays an important role in the control of the oscillations but it is not known whether it acts in the core mechanism of the oscillator. A major aim of this project will be to carry out experiments at the molecular and cellular level to characterize the role of the Notch pathway in the function of the oscillator. We also showed that FGF signaling controls the activation of the segmentation program and the positioning of somitic boundaries in the chick embryo. We intend to establish the implication of the various components of the FGF pathway in this process, and we will examine the interaction of FGF signaling with the Segmentation Clock. Finally, we have provided evidence for a coupling between the Segmentation Clock and the activation or maintenance of Hox genes during axis formation, and we intend to further characterize this interaction during chick embryogenesis. The understanding of the functioning of the Segmentation Clock is of considerable clinical relevance, since in humans mutations in the genes associated with the function of this oscillator such as delta-like 3 (dll3) result in abnormal segmentation of the vertebral column similar to that seen in the spondylocostal dysostosis syndrome.