Signalling Dynamics in Tissue Biology

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Development of an organism from a single cell and its maintenance require tight coordination of cellular processes – this at tissue- and organism-wide level. The function of signalling pathways in mediating this control has long been studied. Only in recent years the function of signalling dynamics could be addressed experimentally.

Studies mainly using single cells have indicated that biological information can be encoded in the dynamics of a signal, the change in signalling activity over time. With new technological advancements, we are now at the stage to study how signalling dynamics function at multicellular level (reviewed in Sonnen and Aulehla 2014).

We apply these tools to study the function and mechanism of dynamic signal encoding during embryonic development and adult tissue homeostasis.

Technologies for the study of signalling dynamics
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We take a multidisciplinary approach combining developmental biology, biochemistry and cell biology with quantitative tools to investigate the function and mechanism of dynamic signal encoding.

We perform fluorescence real-time imaging of dynamic signalling reporters to quantify signalling dynamics at cellular and tissue-wide level.

For functional investigation, we have established a microfluidic system (Sonnen et al. 2018, Sonnen and Merten 2019). This enables the control of signalling dynamics by applying external pathway modulators with high spatiotemporal precision. We can, for instance, manipulate the period of signalling oscillations and to control the phase-relationship between multiple oscillatory signalling pathways. Besides developing microfluidics further, we also apply other tools such as optogenetics for pathway perturbations with high spatiotemporal precision.

(figure reprinted and modified from Cell according to CC BY-NC-ND 4.0, Sonnen et al. 2018)

Development and optimization of in vitro model systems
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To allow for a more straightforward experimental manipulation of the specimen and for ethical reasons, we strive to use in vitro model systems in the lab. Over the last years various groups have established such model systems for embryonic development (e.g. in vitro differentiation of ES cells and gastruloids) and adult tissue (organoids).

Recently, we have worked on the establishment of gastruloids as model system for somitogenesis, the periodic segmentation of the vertebrate embryo, in collaboration with the groups of Alfonso Martinez Arias and Alexander van Oudenaarden. We could for instance show the presence of signalling oscillations in the in vitro structures and optimize the culture in such a way to allow for proper segment formation (van den Brink et al. 2020, Batenburg et al. 2020).

(figure reprinted and modified from Nature, van den Brink et al. 2020)

How do signalling dynamics control embryonic development?
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Somitogenesis is the periodic formation of segments or somites during embryonic development. Somites will give rise to e.g. vertebrae and axial muscles. 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. These are thought to determine the timing of the periodic segmentation. 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 study the molecular mechanism of the segmentation clock and how this controls the periodic segmentation of a growing tissue.

How do signalling dynamics control adult tissue homeostasis?
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Signalling pathways control cell-turnover and differentiation during homeostasis of adult tissue. For instance, homeostasis of the small intestine has been studied extensively and key signalling pathways have been identified. 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, real-time imaging and dynamic manipulation using microfluidics to investigate the function of signalling dynamics governing tissue homeostasis of the small intestine.

How do signalling dynamics impact on disease development and treatment?
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Signalling pathways control diverse processes within organisms ranging from development to regeneration and homeostasis. Therefore, mutations in signalling pathway components can result in for instance developmental malformations or disease development such as cancer.

In the lab we address how changes in signalling dynamics contribute to cancer development and whether they can be targeted for therapy.