Molecular Analysis of the Segmentation Clock

点击翻译按钮获取中文摘要

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.