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Science 308 (5723): 826-833

Copyright © 2005 by the American Association for the Advancement of Science

Functional Genomic Analysis of the Wnt-Wingless Signaling Pathway

Ramanuj DasGupta,1*{dagger} Ajamete Kaykas,2* Randall T. Moon,2{dagger} Norbert Perrimon1{dagger}

Abstract: The Wnt-Wingless (Wg) pathway is one of a core set of evolutionarily conserved signaling pathways that regulates many aspects of metazoan development. Aberrant Wnt signaling has been linked to human disease. In the present study, we used a genomewide RNA interference (RNAi) screen in Drosophila cells to screen for regulators of the Wnt pathway. We identified 238 potential regulators, which include known pathway components, genes with functions not previously linked to this pathway, and genes with no previously assigned functions. Reciprocal-Best-Blast analyses reveal that 50% of the genes identified in the screen have human orthologs, of which ~18% are associated with human disease. Functional assays of selected genes from the cell-based screen in Drosophila, mammalian cells, and zebrafish embryos demonstrated that these genes have evolutionarily conserved functions in Wnt signaling. High-throughput RNAi screens in cultured cells, followed by functional analyses in model organisms, prove to be a rapid means of identifying regulators of signaling pathways implicated in development and disease.

1 Department of Genetics, Howard Hughes Medical Institute (HHMI), Harvard Medical School, New Research Building, No. 339, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
2 HHMI, Department of Pharmacology, Center for Developmental Biology, University of Washington, School of Medicine, Seattle, WA 98195, USA.

Published online 7 April 2005

Include this information when citing this paper.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: rdasgupt{at}genetics.med.harvard.edu (R.D.) or perrimon{at}receptor.med.harvard.edu (N.P.) and rtmoon{at}u.washington.edu (R.T.M.)


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