Originally published as Genetics Published Articles Ahead of Print on January 16, 2006.

Genetics, Vol. 172, 2309-2324, April 2006, Copyright © 2006
doi:10.1534/genetics.104.035170

Presenilin-Based Genetic Screens in Drosophila melanogaster Identify Novel Notch Pathway Modifiers

Matt B. Mahoney^1,2, Annette L. Parks^1,3, David A. Ruddy^1,4, Stanley Y. K. Tiong¹, Hanife Esengil⁵, Alexander C. Phan⁶, Panos Philandrinos⁷, Christopher G. Winter⁸, Runa Chatterjee, Kari Huppert⁹, William W. Fisher¹⁰, Lynn L'Archeveque¹¹, Felipa A. Mapa¹², Wendy Woo, Michael C. Ellis¹³ and Daniel Curtis¹²

Exelixis, South San Francisco, California 94083

³ Corresponding author: Biology Department, Boston College, 140 Commonwealth Ave., Chestnut Hill, MA 02467.
E-mail: annette.parks.1{at}bc.edu

Presenilin is the enzymatic component of -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 -tubulin in the pathway.

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