The evolutionarily conserved Notch-signal transduction has been described as a cell-to-cell signaling pathway mediated by the transmembrane proteins Delta, Jagged and Notch that interact in a ligand-receptor like manner. Notch signaling regulates cell fate decisions and cellular differentiation in various tissues and has essential functions in embryonic patterning and tumorigenesis. Whereas signal transduction to Notch expressing cells and the role of the Notch intracellular domain has been described in detail, the cytoplasmic part of the ligands is less well understood. Several studies demonstrated that also the ligands undergo regulated cleavages leading to the release of the intracellular domain of the ligand into the cytoplasm. Recently, we reported on the identification of proteins interacting with the intracellular domain of Delta1 (Dll1cyto) (Pfister et al., 2003). We have identified several PDZ-domain containing proteins by in vitro and in vivo systems, e.g. from the MAGUK family, that interact with the C-terminal PDZ-binding motif of Delta1. To address these interactions in more detail we generated a conditional mouse mutant targeting the PDZ-binding motif of Delta1 (Dll1DPDZ-bm) and a mouse mutant targeting the Dll1cyto interacting protein Magi2. Here, we will present our newest results regarding the role of the PDZ-binding motif of Delta1.