Natural variation in Monoamine Oxidase A modulates RAS/MAPK pathway activity during C. elegans vulval development

Background: The genetic background has a strong influence on the pathogenesis of many complex, polygenic human diseases. Therefore, detailed genetic studies are needed to decipher the underlying genetic risk factors in human diseases. We use the Nematode C. elegans as a model to study the interplay between cancer-related signaling pathways and genetic background. We focus on the RAS, Notch and WNT pathway genes, whose human orthologues have been shown to be involved in several complex diseases. Obervations: We are addressing the question of how the genetic background influences the output of these signaling networks. For this purpose, we crossed mutants in the RAS pathway originally isolated in the N2 Bristol background into the CB4856 strain isolated in Hawaii and established mutation included recombinant inbred lines (MIRILs). We then measured pathway activity of RAS of each RIL by scoring the number of differentiated vulval cells. A RIL sets containing a mutation in the RAS homologue let-60(gf) in a mixed Hawaii/Bristol background show strong variation in the penetrance and expressivity of the phenotype when compared to the mutant let-60(n1046) in the “pure” Bristol background. This indicates the presence of polymorphic modifiers affecting RAS signaling. Subsequently, we have identified by QTL mapping several genomic regions that contain those modifiers. Using RNAi knockdown and transgenesis, we could identify amx-2, homologous to human MAOA, as being important for suppression of RAS pathway activity. We are now further evaluating the link between the metabolism of biogenic amines such as Serotonin and Dopamine and their role in cancer signaling. Conclusions: By using a quantitative genetics approach, combined with classical genetics we identified amx-2/MAOA as a polymorphic modifier of RAS signaling during C. elegans vulval development.