Structure-function analysis of the mouse Delta1 gene in vivo and in vitro

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Notch signalling is pivotal for the regulation of multiple developmental processes. Notch genes encode transmembrane proteins that act as receptors for Delta and Serrate proteins. These interactions are mediated and modulated by multiple EGF-like repeat modules in the extracellular domains of these proteins. To analyze the significance of particular EGF-like repeats of the mouse Notch ligand Delta1 (Dll1) for the outcome of Notch signalling in vivo we have generated an allelic series of Dll1, in which each of the eight EGF repeats has been mutated individually by replacing conserved Cysteine residues by Glycine. These mutations show a broad spectrum of phenotypic variation, indicating that individual EGF repeats in DLL1 are not equivalent with respect to Notch activation in vivo. The proposed experiments aim at defining the processes affected by individual EGF repeat mutations, and the properties of DLL1 variants with respect to receptor binding and activation in vivo and in vitro. This study will provide insights into the role of particular EGF-like repeats of DLL1 in different developmental contexts during mouse embryogeneis and define regions of DLL1 mediating Notch binding and activation.