Sonnen: Signalling dynamics Back to research group The Sonnen group investigates how signalling pathway dynamics encode information to control development and homeostasis of multicellular systems. Signalling waves during segmentation of mouse embryos How cells communicate and coordinate Cells in multicellular organisms don’t act alone – they must constantly coordinate processes such as growth, specialization, movement, and cell death. From development to adult life, this careful balance ensures proper tissue formation and maintenance, and helps prevent diseases such as cancer. Communication between cells happens through signalling pathways. While these pathways have long been studied as key mediators of cellular control, only in recent years has it become possible to experimentally investigate the role of signalling dynamics — the changes in signalling activity over time. The timing and dynamics of signals are crucial for accurate and efficient coordination between cells. Work in single cells has shown that biological information can be encoded in signal dynamics. Thanks to new technologies and advanced in vitro model systems, we can now study how this dynamic encoding operates at the multicellular level (reviewed in Sonnen and Aulehla 2014). In our lab, we apply these approaches to investigate dynamic signal encoding during early embryonic development, using model systems such as gastruloids, blastoids, and blastocysts. We also study signalling dynamics in tissue homeostasis and regeneration, with a particular focus on the intestine, and explore how disruptions in these processes can drive cancer. To find out more about the lab, also visit our Sonnen Lab website. (figure reprinted and modified from Cell according to CC BY-NC-ND 4.0, Sonnen et al. 2018) What we do The Sonnen lab studies how biological information is transmitted through signalling dynamics in multicellular systems, from early embryonic development to adult tissue homeostasis and disease. We use advanced model systems such as mouse somitogenesis, gastruloids, and blastoids to investigate how dynamic signalling coordinates early development and blastocyst formation. To study tissue maintenance and regeneration, we focus on the small intestine as a model of homeostasis and examine how disruptions in these processes contribute to cancer. Our work combines developmental biology, biochemistry, and cell biology with quantitative approaches. We quantify signalling dynamics using real-time fluorescence imaging in gastruloids, blastoids, and organoids, and complement this with time-resolved proteomics (preprint) and single-cell tracking (preprint) to capture signalling dynamics across scales. A central focus of the lab is the development of new methods to control signalling in space and time. We use microfluidics to precisely manipulate signalling dynamics (Sonnen et al. 2018, Sonnen and Merten 2019) and are establishing optogenetic approaches for targeted, reversible perturbations with high spatiotemporal precision. How do signalling dynamics control embryonic development? Somitogenesis is the periodic formation of somites – the building blocks of vertebrae and axial muscles – during early embryonic development. This sequential segmentation of the presomitic mesoderm (PSM) is regulated by a combination of signalling gradients and oscillations. Oscillatory activity in the Notch, Wnt, and FGF pathways forms the so-called segmentation clock, which determines the timing of somite formation. Our work has shown that critical information for periodic segmentation is encoded not simply in the oscillations themselves, but in the relative timing between Wnt and Notch signalling oscillations (Sonnen et al. 2018). Using single-cell tracking in growing mouse embryos, we also found that coupling of cell proliferation to these signalling oscillations ensure robust somite scaling (preprint). To investigate these mechanisms, we use both in vivo models and advanced in vitro systems. For early development, we study blastocysts and blastoids to explore how signalling dynamics guide the earliest steps of embryogenesis, while gastruloids allow us to model complex processes such as somitogenesis. Together, these approaches help us uncover how dynamic signalling controls tissue patterning and timing during embryonic development, and provide insights into how disruptions in these processes may contribute to disease. How do signalling dynamics control adult tissue homeostasis? In adult tissues, signalling pathways regulate cell turnover and differentiation to maintain homeostasis. A well-studied example is the small intestine, where key pathways controlling stem cell renewal and differentiation have been identified. Yet, the role of signalling dynamics in these processes is still largely unknown. The development of organoid cultures now allows us to grow adult tissues ex vivo, providing a controlled system to study dynamic regulation. By combining organoids with dynamic signalling reporters, real-time imaging, and microfluidic-based perturbations, we can dissect how signalling dynamics govern tissue homeostasis and regeneration. Our recent preprint demonstrates that these tools allow precise monitoring and manipulation of signalling pathways in organoid cultures, revealing how the timing and coordination of signals control tissue maintenance and how disruptions can contribute to cancer. How do signalling dynamics impact on disease development and treatment? Signalling pathways regulate a wide range of processes in the body, from embryonic development to tissue regeneration and homeostasis. Mutations or misregulation of these pathways can lead to developmental disorders or diseases such as cancer. In our lab, we study how changes in signalling dynamics contribute to cancer development and explore whether these dynamic properties can be targeted for therapy. With support from the KWF Dutch Cancer Society, we are investigating how alterations in signalling timing and coordination drive tumor formation and progression. By combining advanced imaging, organoid models, and precise pathway perturbations, we aim to uncover new strategies to intervene in cancer at the level of temporal and spatial signal control.
