ANTINEUROGENIC PHENOTYPES INDUCED BY TRUNCATED NOTCH PROTEINS INDICATE A ROLE IN SIGNAL-TRANSDUCTION AND MAY POINT TO A NOVEL FUNCTION FOR NOTCH IN NUCLEI

Loss of any one of several neurogenic genes of Drosophila results in o verproduction of embryonic neuroblasts at the expense of epidermoblast s. In this paper a variety of altered Notch proteins are expressed in transgenic flies. Dominant lethal, antineurogenic phenotypes were prod uced by expression of three classes of mutant proteins: (1) a protein comprised of the cytoplasmic domain of Notch and devoid of sequences p ermitting membrane association; (2) a transmembrane protein lacking th e extracellular, lin12/Notch repeats; and (3) transmembrane proteins c arrying amino acid substitutions replacing one or both extracellular c ysteines thought to be involved in Notch dimerization. These Notch pro teins not only suppress the neural hypertrophy observed in Notch- embr yos, but also generate a phenotype in which elements of the embryonic nervous system are underproduced. Action of the intracellular cdc10 re peats appears to be essential for wild-type Notch function or for the antineurogenic activity of these proteins. The activities of the domin ant, gain-of-function proteins indicate that Notch functions as a sign al transducing receptor during ectoderm development. Production of ant ineurogenic Notch proteins in embryos deficient for the other neurogen ic genes allowed functional dependencies to be established. Delta, mas termind, bigbrain, and neuralized appear to function in elaboration of a signal upstream of Notch. Genes of the Enhancer of split complex ac t after Notch. The cytoplasmic domain of Notch contains nuclear locali zation sequences that function in cultured cells, and one of the Notch antineurogenic proteins, the cytoplasmic domain, accumulates in nucle i in vivo.