title: A complex regulatory network coordinating cell cycles during C. elegans development is revealed by a genome-wide RNAi screen.
abstract: The development and homeostasis of multicellular animals requires precise coordination of cell division and differentiation. We performed a genome-wide RNA interference screen in Caenorhabditis elegans to reveal the components of a regulatory network that promotes developmentally programmed cell-cycle quiescence. The 107 identified genes are predicted to constitute regulatory networks that are conserved among higher animals because almost half of the genes are represented by clear human orthologs. Using a series of mutant backgrounds to assess their genetic activities, the RNA interference clones displaying similar properties were clustered to establish potential regulatory relationships within the network. This approach uncovered four distinct genetic pathways controlling cell-cycle entry during intestinal organogenesis. The enhanced phenotypes observed for animals carrying compound mutations attest to the collaboration between distinct mechanisms to ensure strict developmental regulation of cell cycles. Moreover, we characterized ubc-25, a gene encoding an E2 ubiquitin-conjugating enzyme whose human ortholog, UBE2Q2, is deregulated in several cancers. Our genetic analyses suggested that ubc-25 acts in a linear pathway with cul-1/Cul1, in parallel to pathways employing cki-1/p27 and lin-35/pRb to promote cell-cycle quiescence. Further investigation of the potential regulatory mechanism demonstrated that ubc-25 activity negatively regulates CYE-1/cyclin E protein abundance in vivo. Together, our results show that the ubc-25-mediated pathway acts within a complex network that integrates the actions of multiple molecular mechanisms to control cell cycles during development.
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Roy
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755.
authors.forename: David V
authors.initials: DV
authors.lastname: Tobin
authors.affiliation: Center for Integrated Protein Science Munich (CiPSM), Biocenter, LMU Munich, 82152 Planegg-Martinsried, Germany.
authors.forename: Nadin
authors.initials: N
authors.lastname: Memar
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Beltz
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755.
authors.forename: Jenna
authors.initials: J
authors.lastname: Holmen
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Clayton
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Chiu
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Young
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755.
authors.forename: Travis H
authors.initials: TH
authors.lastname: Green
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755.
authors.forename: Isabella
authors.initials: I
authors.lastname: Lubin
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Integrated Protein Science Munich (CiPSM), Biocenter, LMU Munich, 82152 Planegg-Martinsried, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Conradt
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755 Norris Cotton Cancer Center, Lebanon, New Hampshire 03756 Richard.M.Saito@Dartmouth.edu.
authors.forename: R Mako
authors.initials: RM
authors.lastname: Saito
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D034622:RNA Interference; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; C475157:UBC-25 protein, C elegans; D014452:Ubiquitins
keywords: C. elegans; cell cycle; development; intestine; regulatory network; ubiquitin-conjugating enzyme