RESUMO
Presenilin is the enzymatic component of gamma-secretase, a multisubunit intramembrane protease that processes several transmembrane receptors, such as the amyloid precursor protein (APP). Mutations in human Presenilins lead to altered APP cleavage and early-onset Alzheimer's disease. Presenilins also play an essential role in Notch receptor cleavage and signaling. The Notch pathway is a highly conserved signaling pathway that functions during the development of multicellular organisms, including vertebrates, Drosophila, and C. elegans. Recent studies have shown that Notch signaling is sensitive to perturbations in subcellular trafficking, although the specific mechanisms are largely unknown. To identify genes that regulate Notch pathway function, we have performed two genetic screens in Drosophila for modifiers of Presenilin-dependent Notch phenotypes. We describe here the cloning and identification of 19 modifiers, including nicastrin and several genes with previously undescribed involvement in Notch biology. The predicted functions of these newly identified genes are consistent with extracellular matrix and vesicular trafficking mechanisms in Presenilin and Notch pathway regulation and suggest a novel role for gamma-tubulin in the pathway.
Assuntos
Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Proteínas de Membrana/genética , Receptores Notch/genética , Alelos , Precursor de Proteína beta-Amiloide/genética , Animais , Cruzamentos Genéticos , Elementos Facilitadores Genéticos , Matriz Extracelular , Feminino , Masculino , Mutação , Presenilina-1 , Receptores Notch/metabolismo , Transdução de Sinais , Tubulina (Proteína)/metabolismoRESUMO
The phenotypic effects in imaginal hypodermal tissue of a number of Abdominal-B mutations of the bithorax complex are described. Evidence is given from complementation analysis that the phenotypic heterogeneity in both the spatial limits and the nature of the homeotic transformations produced is not an arbitrary classification of allelic differences that we find. We have used genetic mosaic analysis to support the interpretation that the Abdominal-B genetic unit can exist in a number of alternative functional states of expression during development and that individual Abdominal-B mutations may abolish some states whilst leaving others unaffected.
