Drosophila Models of RASopathies

Studies in Drosophila were essential in delineating the highly conserved RAS signaling pathway. Indeed, some pathway components, such as Son of sevenless or Corkscrew, were named after mutant phenotypes in flies. Here, we discuss how Drosophila, with its ever-expanding arsenal of precise genetic manipulations and quantitative phenotypic assays, can be harnessed for investigating how RAS signaling is genetically deregulated in human diseases. The general approach is based on analyzing how disease mutations affect well-studied RAS-dependent developmental processes. Focusing on our work in the fly embryo and larval trachea, we illustrate this approach for missense mutations in MEK, a central kinase in the RAS cascade, which is deregulated in developmental abnormalities and cancers. The established approach provides clear insights into genotype/phenotype associations and can be extended to other signaling systems.