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ERC Advanced Grant on genetic interaction analysis

The genetics underlying phenotype-genotype relationships during development and disease is often complex with many genes contributing to a particular phenotypic outcome. While forward genetic screens have uncovered many mutations that are limiting at a particular stage or tissue, the majority of genes in most genomes remain genetically untouched. Recent studies in model organisms, in particular in yeast, have provided evidence for the existence of pervasive genetic interactions with large effects on many phenotypes. Such genetic factors have been rather difficult to identify in classical loss-of-function screens due to buffering and other compensatory mechanisms, therefore requiring novel methodological approaches.

The creation of a synthetic genetic interaction map provides a ground-breaking and unprecedented resource to study genotype-to-phenotype relationships. Multiparametric imaging will allow us to map the epistasis of processes. We utilize the map to globally dissect the interaction between processes with a focus on signaling networks. Furthermore, we  follow-up on selected interactions by in-depth characterization. Synthetic genetic interactions will be further analyzed in vivo in tissues and in human cells.

As part of the ERC project, we are in the process of creating a systematic synthetic genetic interaction map of a metazoan cell. Based on methods that we pioneered, we quantitatively measure genetic interactions using image-based phenotyping between genes. Phenotyping will be performed by multiparametric imaging and pathway-focused reporters. A particular interest is on context-dependent changes in genetic interaction networks and chemico-genetic interactions.

Collaborative Research Center on Mechanisms and Functions of Wnt signaling


Link to SFB1324 Webpage

Wnt signaling pathways play a decisive role in development, cell differentiation, tumorigenesis and tumor progression. Wnt ligands are secreted, lipidated proteins that bind to half a dozen different receptors to activate multiple downstream signaling cascades. Wnt pathways relay signals from divergent ligand-receptor interactions to a network of downstream signaling of conserved cytoplasmic factors. Despite having gained an enormous amount of knowledge about components and mechanisms of Wnt signaling, we are now facing a multitude of new questions about the specificity of signaling input and the control of signaling output during development and in disease.

To advance our understanding of molecular mechanisms governing Wnt signal transduction, the DFG-funded Collaborative Research Center CRC1324 is structured into two major research areas: (A) Wnt secretion, trafficking and receptor-ligand interactions and (B) Wnt coupling to downstream and context-dependent signaling. In the first research area, we want to understand how Wnt ligands are produced, how they are modified and how they are transported in the extracellular space. We also want to unravel the Wnt ligand receptor interactions and understand how they specify the signaling response and induce different signaling cascades. In the second research area, we will focus on the molecular dynamics of the Wnt machinery to understand how different Wnt pathways elicit distinct biological responses and how Wnt signaling is coupled to different downstream factors. We also want to understand the spatio-temporal dynamics of Wnt signaling, i.e., how Wnt signaling regulates oscillations and wave patterns. To address these questions, we will combine a wide range of model systems including hydra, fly, fish, frog, as well as mouse and human cells with cutting-edge technologies including advanced fluorescence microscopy, genetic screens and genome engineering, and proteomics. Our lab is particularly interested in understanding the role of Wnt production and trafficking and the role of Wnt signaling in tumorigenesis.

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