Genetics. Published Articles Ahead of Print: January 16, 2006, Copyright © 2006
doi:10.1534/genetics.104.035170


A more recent version of this article appeared on April 1, 2006.

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

Matt B. Mahoney 1, Annette L. Parks 1*, David A. Ruddy 1, Stanley Y. K. Tiong 1, Hanife Esengil 1, Alexander C. Phan 1, Panos Philandrinos 1, Christopher G. Winter 1, Kari Huppert 1, William W. Fisher 1, Lynn L'Archeveque 1, Felipa A. Mapa 1, Wendy Woo 1, Michael C. Ellis 1 and Daniel Curtis 1

1 Exelixis, Inc

* To whom correspondence should be addressed. E-mail: annette.parks.1{at}bc.edu.

Submitted on September 26, 2005
Revised on October 21, 2005
Accepted on 11 January 2006


Abstract

Presenilin is the enzymatic component of {gamma}-secretase, a multi-subunit 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 which 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.

Key Words: Drosophila, Notch, Presenilin, extracellular matrix, vesicle trafficking




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