Genetic and molecular characterization of a Notch mutation in its Delta- and Serrate-binding domain in Drosophila.

The Drosophila Notch gene product is a transmembrane protein that functions as a receptor of intercellular signals in several Drosophila developmental processes. Two other transmembrane proteins, encoded by the genes Delta and Serrate, genetically and molecularly behave as Notch ligands. All these proteins share the presence of epidermal growth factor (EGF)-like repeats in their extracellular domain. The Notch protein has 36 EGF-like repeats, 2 of which, numbers 11 and 12, are required for the interaction with the Delta and Serrate ligands. We have isolated and molecularly characterized a Notch mutation in its Delta- and Serrate-binding domain that behaves genetically as both a Notch antimorphic and a loss-of-function mutation. This mutation, NM1, carries a Glu-->Val substitution in the Notch EGF repeat 12. The NM1 allele interacts with other Notch alleles such as Abruptex and split and with mutations in the Notch-ligand genes Delta and Serrate. The basis for the genetic antimorphism of NM1 seems to reside in the titration of Notch wild-type products into NM1/N+ nonfunctional dimers and/or the titration of Delta products into nonfunctional ligand-receptor complexes.