Document Type
Article
Publication Date
12-29-2016
Publication Source
Cell Death and Disease
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.
Document Version
Published Version
Copyright
Copyright © 2016, the Authors
Publisher
Nature Publishing Group
Volume
7
Peer Reviewed
yes
Issue
12
Sponsoring Agency
Knight’s Templar Ophthalmology Research Foundation; Ohio Cancer Research Associates
eCommons Citation
Tare, Meghana; Sarkar, Ankita; Bedi, Shimpi; Kango-Singh, Madhuri; and Singh, Amit, "Cullin-4 Regulates Wingless and JNK Signaling-Mediated Cell Death in the Drosophila Eye." (2016). Biology Faculty Publications. 221.
https://ecommons.udayton.edu/bio_fac_pub/221
Included in
Biology Commons, Biotechnology Commons, Cell Biology Commons, Genetics Commons, Microbiology Commons, Molecular Genetics Commons
Comments
Document is provided for download in compliance with the publisher's open-access policy. Permission documentation is on file.
Supplementary Information accompanies this paper on the Cell Death and Disease website (http://www.nature.com/cddis)
Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/