Probing the polygenic basis of cardiomyopathies in Drosophila

In trying to understand the causes for congenital heart disease and cardiomyopathies, it is difficult to study polygenic interactions that contribute to the severity of the disease, which is in part due to genetic complexity and generation time of higher organisms that hinder efficient screening for modifiers of primary causes of heart disease. The adult Drosophila heart has recently been established as a model to probe genetic interactions that lead to cardiac dysfunction in this genetically simple and short-lived organism. This has made it possible to systematically and efficiently screen for polygenic modulators of heart dysfunction inflicted by known heart disease genes. As heart development and fundamental aspects of cardiac physiology show remarkable evolutionary conservation, it has become possible to uncover new heart disease candidates by using Drosophila genetic tools in combination with sensitive heart function assays. Here, we review the discovery of several new genes, genetic pathways, and interactions that will help understand human heart disease. For example, interactions between cardiogenic transcription factors, discovered in Drosophila, are also critical for adult heart function in flies and mammals. These include interactions between tinman/Nkx2-5 and neuromancer/Tbx20, which led to the discovery of possibly disease-causing familial variants in human TBX20. A new genetic pathway from tinman/Nkx2-5 to Cdc42, involving the microRNA miR-1, was recently discovered in flies and subsequently validated to function similarly in mouse heart. Thus, the fly heart has proven to be a useful discovery tool for screening genetic interactions that are otherwise difficult to conduct.