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The Sonnen group investigates how signalling pathway dynamics encode information to control development and homeostasis of multicellular systems.
Signalling pathways coordinate multicellular systems and control cell fate decisions. This way they are absolutely essential to guide embryonic processes such as development, adult tissue homeostasis, regeneration or the immune response. If mutations in signalling pathway components occur, this can for instance result in developmental malformations and disease development such as cancer. Therefore, a long-standing questions in the field of multicellular biology is how signalling pathways function. It has been shown previously that biological information can be encoded in the dynamics (i.e. the temporal change) of a signal. However, most of our knowledge to-date comes from studies using single cells (reviewed in Sonnen and Aulehla 2014). With new technological advancements, we are now at the stage to study how signalling dynamics control development and tissue homeostasis at multicellular level (Sonnen et al. Cell 2018, Sonnen and Merten, Dev Cell 2019). Our work aims at understanding the function and the mechanism of dynamic signal encoding in multicellular systems during embryonic development and adult tissue homeostasis.
Study of signalling dynamics
We take a multidisciplinary, quantitative approach combining developmental biology, biochemistry and cell biology with quantitative tools (such as real-time imaging of dynamic signalling reporters and spatiotemporal perturbations of signalling pathways using microfluidics) to investigate the function of dynamic signalling and the mechanism of dynamic signal encoding at tissue-wide, cellular and molecular levels.
Key questions we ask are:
To address this, we use two model systems: (1) Somitogenesis has been the prime model system for the study of dynamic signal encoding at tissue level. It describes the sequential segmentation of vertebrate embryos, which is controlled by signalling gradients and oscillations. (2) Homeostasis of the small intestine is maintained by the same signalling pathways that govern somitogenesis. We study how signalling pathways contribute to small intestinal homeostasis. We will compare the function of dynamic signal encoding in these two model systems.
Functional investigation of signalling dynamics using microfluidics
For functional dissection of dynamic signal encoding, we have to be able to subtly modulate the dynamics without altering the overall signalling activity and study the effect of such a perturbation. To enable this on multicellular level, we have established a microfluidic system, with which signalling dynamics can be controlled using external pathway modulators with high temporal precision. This setup allows, for instance, to manipulate the period of signalling oscillations and to control the phase-relationship between multiple oscillatory signalling pathways (Figure 3) (Sonnen et al. 2018). We also adapt this system to perform perturbations with high spatial as well as temporal precision. In addition, we apply optogenetics for pathway perturbations with high spatiotemporal precision.
Signalling dynamics during development
Somitogenesis is the periodic formation of segments or somites, which give rise to e.g. vertebrae and axial muscles, during embryonic development. Sequential segmentation of the presomitic mesoderm (PSM) is controlled by both signalling gradients and oscillations. Oscillatory Notch, Wnt and FGF signalling constitute the so-called “segmentation clock” and are thought to determine the timing of the periodic segmentation (see video below). We have shown previously that critical information for periodic segmentation of the PSM is encoded in the relative timing of Wnt and Notch signalling oscillations (Sonnen et al. 2018).
We aim to understand the molecular mechanism of how Wnt, Notch and FGF signalling pathways are linked and control the periodic segmentation of the PSM. We also address how signalling pathway oscillations interact with other oscillatory systems, i.e. the cell cycle machinery (Figure 4). This will advance our understanding of the coordination of growth and patterning during development (Figure 2).
Signalling dynamics during adult tissue homeostasis
Signalling pathways control cell-turnover and differentiation during tissue homeostasis to constantly renew adult tissues. However, the function of signalling dynamics in these processes is still largely unknown.
The recent establishment of “organoid” cultures has enabled the ex vivo cultivation of adult tissues. We combine organoid culture with dynamic signalling reporters (Figure 5), real-time imaging and dynamic manipulation using microfluidics to investigate the function of signalling pathways governing cell turnover and differentiation at a dynamic and quantitative level (Figure 2).
Sonnen KF, Merten CA
Sonnen KF, Lauschke V, Uraji J, Falk H J, Petersen Y, Funk MC, Beaupeux M, François P, Merten CA and Aulehla A.
Bulusu V, Prior N, Snaebjornsson MT, Kuehne A, Sonnen KF, Kress J, Stein F, Schultz C, Sauer U and Aulehla A.
Sonnen KF and Aulehla A.
Sonnen KF, Gabryjonczyk AM, Anselm E, Stierhof YD and Nigg EA.
Sonnen KF, Schermelleh L, Leonhardt H, Nigg EA
Katharina Sonnen is group leader at the Hubrecht Institute. Her group studies how biological information is robustly transmitted via signalling pathway dynamics in multicellular systems. They focus on the role of signalling pathway dynamics (1) during development using mouse somitogenesis as model system and (2) during tissue homeostasis using intestinal organoids as model system. The Sonnen group uses techniques to perturb and quantitatively analyse the dynamics of signalling pathways. They have established a microfluidic system to dynamically modulate intercellular signalling in multicellular systems. In addition, they complement those tools with biochemical and cell biological techniques to unravel the mechanism of dynamic signal encoding at the molecular level.
Scientific training and positions
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We are currently interested in recruiting highly motivated and enthusiastic people who are interested in working on an interdisciplinary research project on the functional analysis of signalling dynamics at tissue level. We are looking for applicants from diverse backgrounds, such as developmental biology, cell biology, biochemistry and bioengineering.
If you want to learn more about available positions, please send an email to Katharina Sonnen including a CV (with grades), a cover letter and contact information for 3 potential references.
We have several exciting projects available for Master students. Please email Katharina Sonnen if you are interested in an internship in our group.