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.
Highlights
During organogenesis, regulation of conserved processes like cell proliferation, cell survival and cell death is crucial for organ growth and differentiation
Wg is required for patterning, growth regulation and cell survival in multiple tissues including the eye discs
We found that cells lacking cul-4 function undergo cell death and they express high levels of Wg
Summary
Regulation of conserved processes like cell proliferation, cell survival and cell death is crucial for organ growth and differentiation. We used Drosophila eye model to identify genes involved in promoting growth and cell survival. We argued that during early eye development, Wg or JNK levels must be tightly regulated to allow differentiation to proceed, and to prevent premature cell death that results in small or reduced eye phenotype. The cul-4 gene belongs to an evolutionary conserved class of Cullin-family E3 ubiquitin ligases.[32] Earlier studies showed that cul-4 is involved in maintenance of genomic integrity by promoting the ubiquitylation and subsequent degradation of key regulators of cell cycle progression.[33,34,35,36] Here, we report that cul-4 promotes cell survival by preventing Wg and JNK signaling-mediated cell death in the developing eye
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