title: A genome-wide RNA interference screen in Drosophila melanogaster cells for new components of the Hh signaling pathway.
abstract: Members of the Hedgehog (Hh) family of signaling proteins are powerful regulators of developmental processes in many organisms and have been implicated in many human disease states. Here we report the results of a genome-wide RNA interference screen in Drosophila melanogaster cells for new components of the Hh signaling pathway. The screen identified hundreds of potential new regulators of Hh signaling, including many large protein complexes with pleiotropic effects, such as the coat protein complex I (COPI) complex, the ribosome and the proteasome. We identified the multimeric protein phosphatase 2A (PP2A) and two new kinases, the D. melanogaster orthologs of the vertebrate PITSLRE and cyclin-dependent kinase-9 (CDK9) kinases, as Hh regulators. We also identified a large group of constitutive and alternative splicing factors, two nucleoporins involved in mRNA export and several RNA-regulatory proteins as potent regulators of Hh signal transduction, indicating that splicing regulation and mRNA transport have a previously unrecognized role in Hh signaling. Finally, we showed that several of these genes have conserved roles in mammalian Hh signaling.
authors.affiliation: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. knybakke@receptor.med.harvard.edu
authors.forename: Kent
authors.initials: K
authors.lastname: Nybakken
authors.forename: Steven A
authors.initials: SA
authors.lastname: Vokes
authors.forename: Ting-Yi
authors.initials: TY
authors.lastname: Lin
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
authors.forename: Norbert
authors.initials: N
authors.lastname: Perrimon
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D017344:Genes, Insect; D049750:Genome, Insect; D023281:Genomics; D053823:Hedgehog Proteins; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2; D034622:RNA Interference; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D019476:Insect Proteins; D012333:RNA, Messenger; C077245:hh protein, Drosophila; D010770:Phosphotransferases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C079898:tws protein, Drosophila