title: Cullin-4 regulates Wingless and JNK signaling-mediated cell death in the Drosophila eye.
abstract: In all multicellular organisms, the fundamental processes of cell proliferation and cell death are crucial for growth regulation during organogenesis. Strict regulation of cell death is important to maintain tissue homeostasis by affecting processes like regulation of cell number, and elimination of unwanted/unfit cells. The developing Drosophila eye is a versatile model to study patterning and growth, where complex signaling pathways regulate growth and cell survival. However, the molecular mechanisms underlying regulation of these processes is not fully understood. In a gain-of-function screen, we found that misexpression of cullin-4 (cul-4), an ubiquitin ligase, can rescue reduced eye mutant phenotypes. Previously, cul-4 has been shown to regulate chromatin remodeling, cell cycle and cell division. Genetic characterization of cul-4 in the developing eye revealed that loss-of-function of cul-4 exhibits a reduced eye phenotype. Analysis of twin-spots showed that in comparison with their wild-type counterparts, the cul-4 loss-of-function clones fail to survive. Here we show that cul-4 clones are eliminated by induction of cell death due to activation of caspases. Aberrant activation of signaling pathways is known to trigger cell death in the developing eye. We found that Wingless (Wg) and c-Jun-amino-terminal-(NH2)-Kinase (JNK) signaling are ectopically induced in cul-4 mutant clones, and these signals co-localize with the dying cells. Modulating levels of Wg and JNK signaling by using agonists and antagonists of these pathways demonstrated that activation of Wg and JNK signaling enhances cul-4 mutant phenotype, whereas downregulation of Wg and JNK signaling rescues the cul-4 mutant phenotypes of reduced eye. Here we present evidences to demonstrate that cul-4 is involved in restricting Wg signaling and downregulation of JNK signaling-mediated cell death during early eye development. Overall, our studies provide insights into a novel role of cul-4 in promoting cell survival in the developing Drosophila eye.
authors.affiliation: Department of Biology, University of Dayton, Dayton, OH, USA.
authors.forename: Meghana
authors.initials: M
authors.lastname: Tare
authors.affiliation: Department of Biology, University of Dayton, Dayton, OH, USA.
authors.forename: Ankita
authors.initials: A
authors.lastname: Sarkar
authors.affiliation: Department of Biology, University of Dayton, Dayton, OH, USA.
authors.forename: Shimpi
authors.initials: S
authors.lastname: Bedi
authors.affiliation: Department of Biology, University of Dayton, Dayton, OH, USA.|Premedical Program, University of Dayton, Dayton, OH, USA.|Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, Dayton, OH, USA.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Kango-Singh
authors.affiliation: Department of Biology, University of Dayton, Dayton, OH, USA.|Premedical Program, University of Dayton, Dayton, OH, USA.|Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, Dayton, OH, USA.|Center for Genomic Advocacy (TCGA), Indiana State University, Terre Haute, IN, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Singh
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival; D044842:Cullin Proteins / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000201:enzymology*; D004789:Enzyme Activation; D005123:Eye / Q000166:cytology* / Q000201:enzymology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D016019:Survival Analysis; D051155:Wnt1 Protein / Q000378:metabolism
chemical_list: C524852:Cul4 protein, Drosophila; D044842:Cullin Proteins; D029721:Drosophila Proteins; D051155:Wnt1 Protein; C074622:wg protein, Drosophila; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases