Functional analysis of the atypical DSL protein DLL3

点击翻译按钮获取中文摘要

The Notch signaling pathway is an evolutionary conserved mechanism mediating the direct communication between adjacent cells. Notch signaling is pivotal for the regulation of multiple developmental processes in diverse organisms such as nematodes, insects and vertrebrates. Recent studies in vertebrate embryos have demonstrated an essential role for Notch signaling in somite formation and patterning. Disruption of Notch signaling causes severe defects during somitogenesis: boundaries are misaligned and irregular, somite polarity is abolished or perturbed, and segment borders are not maintained. Two of the five ligands for Notch in mouse, Delta1 (Dll1) and Delta3 (Dll3), have essential functions during somitogenesis. However, despite the largely overlapping expression of Dll1 and Dll3 in the presomitic mesoderm, null alleles of both Dll1 (Dll1lacZ) and Dll3 (Dll3pu) affect patterning processes in the presomitic mesoderm differently, suggesting that Dll1 and Dll3 have distinct, non-redundant functions during somite formation. In this study we propose to test the hypothesis that Dll1 and Dll3 have non-redundant functions especially during somitogenesis, and that the specific functions of Dll1 and Dll3 are brought about by different biochemical properties. This will be achieved by replacing Dll1 with the coding sequence of Dll3 and analysis of mice carrying this gene replacement, and biochemical characterization of the interaction of Dll1 and Dll3 with Notch receptors in vitro. These experiments should further elucidate the functions and biochemical properties of the Notch ligands Dll1 and Dll3 and help to understand their functions in the paraxial mesoderm and the basic molecular mechanisms underlying mesoderm segmentation in mammals.