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Updated: Aug 17, 2026
The Drosophila Imaginal Disc Tumor Model: Visualization and Quantification of Gene Expression and Tumor Invasiveness Using Genetic Mosaics
Published on: October 6, 2016
A Drosophila model of multiple endocrine neoplasia type 2
Renee D Read1, Paul J Goodfellow, Elaine R Mardis
1Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Abstract:
Dominant mutations in the Ret receptor tyrosine kinase lead to the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Mammalian tissue culture studies suggest that RetMEN2 mutations significantly alter Ret-signaling properties, but the precise mechanisms by which RetMEN2 promotes tumorigenesis remain poorly understood. To determine the signal transduction pathways required for RetMEN2 activity, we analyzed analogous mutations in the Drosophila Ret ortholog dRet. Overexpressed dRetMEN2 isoforms targeted to the developing retina led to aberrant cell proliferation, inappropriate cell fate specification, and excessive Ras pathway activation. Genetic analysis indicated that dRetMEN2 acts through the Ras-ERK, Src, and Jun kinase pathways. A genetic screen for mutations that dominantly suppress or enhance dRetMEN2 phenotypes identified new genes that are required for the phenotypic outcomes of dRetMEN2 activity. Finally, we identified human orthologs for many of these genes and examined their status in human tumors. Two of these loci showed loss of heterozygosity (LOH) within both sporadic and MEN2-associated pheochromocytomas, suggesting that they may contribute to Ret-dependent oncogenesis.
Insights
Dominant mutations in the Ret receptor tyrosine kinase (Ret) cause multiple endocrine neoplasia type 2 (MEN2). This study used Drosophila to reveal RetMEN2 activates Ras-ERK, Src, and Jun kinase pathways, identifying new cancer-related genes.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Dominant mutations in the Ret receptor tyrosine kinase (Ret) cause the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2).
- The precise mechanisms by which RetMEN2 mutations promote tumorigenesis are not fully understood.
- Previous studies in mammalian tissue culture suggest altered Ret-signaling properties.
Purpose of the Study:
- To determine the signal transduction pathways required for RetMEN2 activity.
- To identify novel genes involved in RetMEN2-driven tumorigenesis.
- To investigate the role of these genes in human tumors.
Main Methods:
- Utilized Drosophila melanogaster as a model organism to study RetMEN2 mutations.
- Overexpressed dRetMEN2 isoforms in the developing retina.
- Performed genetic analysis of Ras-ERK, Src, and Jun kinase pathways.
- Conducted a genetic screen to identify suppressors and enhancers of dRetMEN2 phenotypes.
- Identified human orthologs and analyzed their status in human pheochromocytomas.
Main Results:
- Overexpression of dRetMEN2 in Drosophila retina caused aberrant cell proliferation, abnormal cell fate specification, and excessive Ras pathway activation.
- Genetic analysis confirmed dRetMEN2 acts through Ras-ERK, Src, and Jun kinase pathways.
- A genetic screen identified novel genes essential for dRetMEN2 phenotypes.
- Two identified human orthologs showed loss of heterozygosity in sporadic and MEN2-associated pheochromocytomas.
Conclusions:
- Drosophila Ret ortholog dRetMEN2 activates key signaling pathways (Ras-ERK, Src, Jun kinase) implicated in tumorigenesis.
- The study identified novel genes involved in Ret-dependent oncogenesis.
- Loss of heterozygosity in specific human orthologs suggests their potential role in pheochromocytoma development.
