A Drosophila model for the functional analysis of Ski/Sno proteins in the context of cell differentiation and tumorigenesis

• Applicant: Dr. Susanne Fischer
• Subject Area: Developmental Biology ; Evolutionary Cell and Developmental Biology (Zoology)
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289981762

Ski/Sno-proteins are known as proto-oncogenes involved in various signalling pathways e.g. in negative regulation of Transforming Growth Factors-ß (TGF-ß) and Bone Morphogenetic Proteins (BMP signalling). This family of proteins is highly conserved between vertebrates and invertebrates and is involved in numerous developmental and homeostatic mechanisms like cell differentiation, determination or apoptosis. In addition, deregulated Ski/Sno-proteins are associated with malignant transformation or metastasis. However, many important aspects of their cellular and molecular functions are still unknown. The aim of this proposal is a functional analysis of Fussel, a new member of the SkiSno-protein family in Drosophila, which, due to its strong conservation to the human protein, is of general importance to the understanding of Ski/Sno-proteins. Extensive preliminary studies enabled us to develop all the tools and possibilities to undertake a comprehensive analysis of the molecular and cellular function of Fussel, which should allow us now to discover important functional concepts of this protein family. In the first part of this proposal we would like to identify the cell- and developmental functions of Fussel in the process of determination and differentiation of specific neurons. Using newly discovered Fussel mutations, we would like to analyze the importance of this gene in developmental mechanisms like cell identity, cell differentiation and neuronal connections. As part of this project we will also examine the hypothesis, that important endogenous function of Fussel are not simply due to negative regulation of BMB-signaling, but rather involve multiple independent signalling mechanisms. Ski/Sno-proteins act via chromatin-bound protein complexes, the composition of which, at least in the case of Fussel, is still largely unknown. In the second part of this proposal, we would like to identify important members of this protein-complex by using genetic and biochemical methods largely established in our lab. These methods allowed us already to identify Medea (Smad4) as one of the members of this complex. In the last part of this proposal we would like to test the function of Fussel as a potential oncogene. With our established model of ectopic expression of Fussel in the developing eye, we would like to further analyze hyperproliferation in the eye disc and its possible tumorigenic potential. Our intensive preliminary studies have enabled us to establish numerous molecular, genetic and histological tools and we now have the unique opportunity to develop a comprehensive understanding of the function of these proteins in the context of endogenous cellular function and tumorigenesis.

• DFG Programme: Research Grants