Presenilin-based genetic screens in Drosophila melanogaster identify novel notch pathway modifiers.
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.
Mahoney
Matt B
MB
Exelixis, South San Francisco, California 94083.
Parks
Annette L
AL
Ruddy
David A
DA
Tiong
Stanley Y K
SY
Esengil
Hanife
H
Phan
Alexander C
AC
Philandrinos
Panos
P
Winter
Christopher G
CG
Chatterjee
Runa
R
Huppert
Kari
K
Fisher
William W
WW
L'Archeveque
Lynn
L
Mapa
Felipa A
FA
Woo
Wendy
W
Ellis
Michael C
MC
Curtis
Daniel
D
D000483:Alleles; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D003433:Crosses, Genetic; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D005109:Extracellular Matrix; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D053764:Presenilin-1; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014404:Tubulin / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D029721:Drosophila Proteins; D008565:Membrane Proteins; C497759:N protein, Drosophila; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051880:Receptors, Notch; D014404:Tubulin