Specification and diversification of cardiac cell subtypes in Drosophila

• Applicant: Dr. Ingolf Reim
• Subject Area: Developmental Biology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 422738372

The heart is a sophisticated organ that needs different kinds of specialized cells to function properly. The properties of each cell are determined by its gene activities and position within the organ. Complex regulatory mechanisms have evolved to ensure that all of the required cell types are correctly specified and arranged in a stereotyped pattern during embryonic development. Mutations in genes implicated in these developmental programs may lead to congenital heart disease. Extensive research (including studies in several vertebrate and invertebrate model organisms) has lead to the identification of key regulatory genes involved in normal or abnormal heart formation, most of which encode transcription factors and components of cell signaling pathways that are conserved from insects to humans. To understand how these gene activities coordinate cardiogenesis, in particular how they interact to generate alternate cardiac cell fates in multipotent precursors, much more work is necessary. We want to elucidate the mechanisms of heart cell diversification in the fruit fly Drosophila. This model organism allows the application of a vast assortment of genetic methods in combination with molecular and imaging analysis. Drosophila possesses a relatively simple, yet diversified heart with a highly stereotyped pattern of different heart cells. This project focuses on the progenitors of its two major heart muscle cell types: generic cardioblasts of the working myocardium and inflow valve-forming ostial cardioblasts.In an unbiased genetic screen and its follow-up work, we have recently identified Epidermal Growth Factor (EGF)-induced MAPK signaling, the ETS family transcriptional activator Pointed (Pnt) and its antagonist ETS domain lacking (Edl) as key players in the gene-regulatory network controlling cardioblast diversification. Extensive genetic studies enabled us to devise a novel model for this process. In this project we want to address important yet unresolved questions of the model: What is the exact timing and direction of the signaling events in the cardiogenic mesoderm and how are the differential activities in cardiac progenitors regulated? In quest for the primary signal responsible for initial signaling asymmetries, we will investigate how MAPK signaling-related gene activities and subsequent cell fate choices are influenced by segmental inputs using novel tissue-specific approaches. Furthermore, we will investigate downstream aspects of the cardiac MAPK-Pnt pathway by searching for additional targets and looking into potential cross-regulation between different growth factor signaling cascades. We expect the results from this project to be very helpful not only for investigating the earliest events of cardiac lineage diversification in Drosophila, but also for understanding many other developmental processes, since the genes investigated in this project are repeatedly expressed during development in most multicellular organisms.

• DFG Programme: Research Grants