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Presenilin-based genetic screens in Drosophila melanogaster identify novel notch pathway modifiers.

Mahoney MB, Parks AL, Ruddy DA, Tiong SY, Esengil H, Phan AC, Philandrinos P, Winter CG, Chatterjee R, Huppert K, Fisher WW, L'Archeveque L, Mapa FA, Woo W, Ellis MC, Curtis D
Genetics. 2006 172 (4): 2309-24

PMID: 16415372 · PMCID: PMC1456381 · DOI:10.1534/genetics.104.035170

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.

MeSH Terms (16)

Alleles Amyloid beta-Protein Precursor Animals Crosses, Genetic Drosophila melanogaster Drosophila Proteins Enhancer Elements, Genetic Extracellular Matrix Female Male Membrane Proteins Mutation Presenilin-1 Receptors, Notch Signal Transduction Tubulin

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