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SFB 1324:  Mechanisms and functions of Wnt signaling

Subject Area Biology
Term since 2017
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Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 331351713
 
Over the past two decades, Heidelberg and the Rhine-Neckar area have become a world-leading hub for Wnt signaling research, with CRC 1324 at its center. CRC 1324 aims to mechanistically and quantitatively understand how Wnt signals are produced, sensed, and translated into context-dependent responses during development and disease. Using model organisms and human disease systems, we explore conserved and diversified features of Wnt signaling across scales, linking pathway regulation to function in health and pathology.Wnt ligands are lipidated, secreted proteins that bind various receptors to activate conserved cytoplasmic cascades. Wnt pathways govern embryonic patterning, stem cell maintenance, tissue homeostasis, and aging, and are implicated in many human diseases. Despite the identification of key components, fundamental questions remain about spatial and temporal regulation, signaling specificity, and context-dependent downstream responses. Wnt signaling is thus both a paradigmatic signal transduction model and a target for therapeutic intervention.CRC 1324’s strategy involves cross-species analysis of Wnt secretion, receptor engagement, and downstream coupling. Using Hydra, Drosophila, Xenopus, zebrafish, mouse, and human systems, we apply multiscale imaging, proteomics, structural biology, single-cell omics, and modeling to reveal conserved mechanisms and accelerate translational insight.In the first funding period, CRC 1324 integrated quantitative approaches into developmental and human models, e.g., measuring ligand-receptor affinities in live cells via axial line-scanning fluorescence correlation spectroscopy. In the second period, we expanded to include Heidelberg groups focused on Wnt-driven diseases, intensified interdisciplinary collaboration, and addressed the regulation of Wnt signaling in space and time at organismal levels. In the third funding period, we will link mechanistic insights, on ligand biogenesis, signal regulation, metabolic integration, mechanobiology, and stem cell plasticity, to disease-relevant models. This mechanism-to-model continuum ensures that molecular and structural insights are tested in relevant biological contexts. Building on established collaborations, we refine projects and formulate new questions connecting pathway analysis to in vivo function in oncology, cardiology, and nephrology.CRC 1324 is structured into two mechanism-based research areas: (A) Wnt secretion and receptor-ligand interactions: We study how Wnt proteins are modified, secreted, and trafficked, focusing on cell-type specific secretion and receptor codes. (B) Wnt coupling to downstream and context-specific signaling: We examine how distinct pathways elicit specific outcomes, using imaging and single-cell approaches to define dynamic regulation and metabolic influences.CRC 1324 combines mechanistic depth with translational reach to define how dynamic Wnt architectures govern development, tissue function, and disease.
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Spokespersons Professor Dr. Michael Boutros, since 7/2021; Professor Dr. Thomas W. Holstein, until 6/2021
 
 

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