The APC/C Coordinates Retinal Differentiation with G1 Arrest through the Nek2-Dependent Modulation of Wingless Signaling

• Published in: Developmental cell Vol. 40; no. 1; pp. 67 - 80
• Main Authors: Martins, Torcato, Meghini, Francesco, Florio, Francesca, Kimata, Yuu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.01.2017; Cell Press
• Subjects: Anaphase-Promoting Complex-Cyclosome - metabolism; Animals; APC/C; Apoptosis; Cell Differentiation; differentiation; Down-Regulation; Dpp; Drosophila; Drosophila melanogaster - cytology; Drosophila melanogaster - metabolism; Drosophila Proteins - metabolism; eye development; fate specification; G1 Phase Cell Cycle Checkpoints; Imaginal Discs - cytology; Imaginal Discs - metabolism; Nek2; Phenotype; Protein Subunits - metabolism; Protein-Serine-Threonine Kinases - metabolism; Proteolysis; Retina - cytology; Signal Transduction; Substrate Specificity; wingless; Wnt; Wnt1 Protein - metabolism; APC/C; differentiation; Dpp; fate specification; Drosophila; wingless; eye development; Nek2; Wnt; proteolysis
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2016.12.005

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. [Display omitted] •APC/C inactivation disrupts retinal differentiation in the Drosophila eye•APC/C inactivation causes the ectopic activation of Wg signaling•APC/CFzr downregulates a Wg modulator, dNek2, by proteolysis upon G1 arrest•Local dNek2 degradation ensures the coordination of retinal differentiation Martins et al. discovered a cell-cycle-independent function of the APC/C ubiquitin ligase in Drosophila eye development. They show that the APC/C controls retinal differentiation by locally suppressing Wingless signaling through the destruction of Nek2. Thus, the APC/C coordinates developmental signaling activity with the cell cycle.