Sonnen: Signalling dynamics

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The Sonnen group investigates how signalling pathway dynamics encode information to control development and homeostasis of multicellular systems.

Figure 1: Transmitting biological information with signalling dynamics. Information can be encoded in the dynamics of a signalling pathway, for instance in oscillations. The signal can be decoded by reading out the signal in a static (e.g. absolute level at the timepoint highlighted with dashed line) or a dynamic manner.

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.

For further details also see our Sonnen Lab website.

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:

  1. How do signalling dynamics control growth and patterning during embryonic development?
  2. How do signalling dynamics affect cell turnover and differentiation during homeostasis of adult tissues?

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.

Figure 3: Microfluidic system enables manipulation of dynamic signalling in primary tissue cultures. Microfluidic setup consists of self-made PDMS chip, which is perfused with microfluidic pumps allowing primary tissue culture on-chip and simultaneous real-time imaging. (Figure adapted from Sonnen et al. 2018.)

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.

Figure 4: Mouse somitogenesis is the periodic segmentation of a growing tissue. While the influence of signalling pathways on segmentation and patterning has been studied for decades, the control of cell proliferation within segmenting presomitic mesoderm is not understood in detail.

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).

Figure 5: Visualization of Wnt signalling activity in organoids of the mouse small intestine. Paneth cells (labelled with asterisks) provide Wnt protein to induce Wnt signalling in neighbouring cells, which can be visualized using a dynamic Wnt signalling reporter.

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).