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Updated: Jun 19, 2025
Microinjection Wound Assay and In vivo Localization of Epidermal Wound Response Reporters in Drosophila Embryos.
Published on: November 1, 2013
Wnt signaling modulates the response to DNA damage in the Drosophila wing imaginal disc by regulating the EGFR
Ben Ewen-Campen1, Norbert Perrimon1,2
1Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
Abstract:
Despite the deep conservation of the DNA damage response (DDR) pathway, cells in different contexts vary widely in their susceptibility to DNA damage and their propensity to undergo apoptosis as a result of genomic lesions. One of the cell signaling pathways implicated in modulating the DDR is the highly conserved Wnt pathway, which is known to promote resistance to DNA damage caused by ionizing radiation in a variety of human cancers. However, the mechanisms linking Wnt signal transduction to the DDR remain unclear. Here, we use a genetically encoded system in Drosophila to reliably induce consistent levels of DNA damage in vivo, and demonstrate that canonical Wnt signaling in the wing imaginal disc buffers cells against apoptosis in the face of DNA double-strand breaks. We show that Wg, the primary Wnt ligand in Drosophila, activates epidermal growth factor receptor (EGFR) signaling via the ligand-processing protease Rhomboid, which, in turn, modulates the DDR in a Chk2-, p53-, and E2F1-dependent manner. These studies provide mechanistic insight into the modulation of the DDR by the Wnt and EGFR pathways in vivo in a highly proliferative tissue. Furthermore, they reveal how the growth and patterning functions of Wnt signaling are coupled with prosurvival, antiapoptotic activities, thereby facilitating developmental robustness in the face of genomic damage.
Insights
Canonical Wnt signaling protects cells from DNA damage-induced apoptosis by activating EGFR signaling. This pathway, involving Rhomboid, Chk2, p53, and E2F1, enhances developmental robustness against genomic lesions.
Area of Science:
- Cellular biology
- Developmental biology
- Genetics
Background:
- The DNA damage response (DDR) pathway is conserved but cellular susceptibility to DNA damage varies.
- The Wnt pathway is implicated in modulating DDR and promoting resistance to DNA damage in cancers.
- Mechanisms linking Wnt signaling to DDR are not fully understood.
Purpose of the Study:
- To elucidate the mechanisms by which Wnt signaling modulates the DNA damage response in vivo.
- To investigate the role of Wnt signaling in buffering cells against apoptosis following DNA double-strand breaks.
Main Methods:
- Utilized a genetically encoded system in Drosophila to induce DNA damage in vivo.
- Investigated the activation of epidermal growth factor receptor (EGFR) signaling by Wnt ligand (Wg) via Rhomboid.
- Analyzed the modulation of DDR in a Chk2-, p53-, and E2F1-dependent manner.
Main Results:
- Canonical Wnt signaling in Drosophila wing imaginal discs protects cells from apoptosis induced by DNA double-strand breaks.
- Wg activates EGFR signaling through Rhomboid, which influences the DDR.
- The DDR modulation by Wnt and EGFR pathways is dependent on Chk2, p53, and E2F1.
Conclusions:
- Wnt signaling is coupled with prosurvival, antiapoptotic activities in highly proliferative tissues.
- EGFR signaling is a key mediator linking Wnt signal transduction to the DDR.
- These findings provide mechanistic insight into developmental robustness in the face of genomic damage.
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