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Published Online April 7, 2005
Science DOI: 10.1126/science.1109374

Research Articles

Submitted on January 4, 2005
Accepted on March 2, 2005

Functional Genomic Analysis of the Wnt-Wingless Signaling Pathway

Ramanuj DasGupta 1, Ajamete Kaykas 2, Randall T. Moon 2, Norbert Perrimon 1*

1 Department of Genetics, Howard Hughes Medical Institute (HHMI), Harvard Medical School, NRB 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.

* To whom correspondence should be addressed.
Norbert Perrimon , E-mail: perrimon{at} receptor.med.harvard.edu

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, proves to be a rapid means of identifying regulators of signaling pathways implicated in development and disease.


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