Functional genomic analysis of the Wnt-wingless signaling pathway

Science. 2005 May 6;308(5723):826-33. doi: 10.1126/science.1109374. Epub 2005 Apr 7.

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 approximately 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line
  • Cloning, Molecular
  • Computational Biology
  • Cytoskeletal Proteins / metabolism
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / metabolism
  • Embryo, Nonmammalian / metabolism
  • Embryonic Development
  • Epistasis, Genetic
  • Gene Expression Regulation*
  • Genes, Insect
  • Genes, Reporter
  • Genomics*
  • Mutation
  • Phenotype
  • Phosphorylation
  • Protein Kinases / metabolism
  • Proteins / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA Interference*
  • Signal Transduction*
  • Trans-Activators / metabolism
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transfection
  • Wnt Proteins
  • Wnt1 Protein
  • Wnt3 Protein
  • Zebrafish
  • Zebrafish Proteins
  • beta Catenin
  • rab5 GTP-Binding Proteins / genetics
  • rab5 GTP-Binding Proteins / metabolism

Substances

  • Cytoskeletal Proteins
  • Drosophila Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • Wnt Proteins
  • Wnt1 Protein
  • Wnt3 Protein
  • Zebrafish Proteins
  • beta Catenin
  • ctnnb1 protein, zebrafish
  • wg protein, Drosophila
  • Protein Kinases
  • rab5 GTP-Binding Proteins