title: The APC/C Coordinates Retinal Differentiation with G1 Arrest through the Nek2-Dependent Modulation of Wingless Signaling.
abstract: The cell cycle is coordinated with differentiation during animal development. Here we report a cell-cycle-independent developmental role for a master cell-cycle regulator, the anaphase-promoting complex or cyclosome (APC/C), in the regulation of cell fate through modulation of Wingless (Wg) signaling. The APC/C controls both cell-cycle progression and postmitotic processes through ubiquitin-dependent proteolysis. Through an RNAi screen in the developing Drosophila eye, we found that partial APC/C inactivation severely inhibits retinal differentiation independently of cell-cycle defects. The differentiation inhibition coincides with hyperactivation of Wg signaling caused by the accumulation of a Wg modulator, Drosophila Nek2 (dNek2). The APC/C degrades dNek2 upon synchronous G1 arrest prior to differentiation, which allows retinal differentiation through local suppression of Wg signaling. We also provide evidence that decapentaplegic signaling may posttranslationally regulate this APC/C function. Thus, the APC/C coordinates cell-fate determination with the cell cycle through the modulation of developmental signaling pathways.
authors.affiliation: Cell Cycle Development Group, Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK. Electronic address: tjn29@cam.ac.uk.
authors.forename: Torcato
authors.initials: T
authors.lastname: Martins
authors.affiliation: Cell Cycle Development Group, Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Meghini
authors.affiliation: Cell Cycle Development Group, Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Florio
authors.affiliation: Cell Cycle Development Group, Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK. Electronic address: yk299@cam.ac.uk.
authors.forename: Yuu
authors.initials: Y
authors.lastname: Kimata
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints; D060227:Imaginal Discs / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D059748:Proteolysis; D012160:Retina / Q000166:cytology*; D015398:Signal Transduction; D013379:Substrate Specificity; D051155:Wnt1 Protein / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D021122:Protein Subunits; D051155:Wnt1 Protein; C074622:wg protein, Drosophila; D064173:Anaphase-Promoting Complex-Cyclosome; C000620809:Nek2 protein, Drosophila; D017346:Protein Serine-Threonine Kinases
keywords: APC/C; Dpp; Drosophila; Nek2; Wnt; differentiation; eye development; fate specification; proteolysis; wingless