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Signaling dynamics in the control of cell proliferation and differentiation during development and homeostasis

Project description

Cell signaling dynamics in proliferation and differentation

Coordination of proliferation and differentiation is necessary for the development and homeostasis of multicellular organisms. While signalling pathways have long been studied in this control, the role of signalling dynamics has only recently been indicated. Key questions remain about the functions and mechanisms of signalling dynamics in controlling proliferation and differentiation at tissue level. This EU-funded project will use a multidisciplinary approach combining expertise in signalling dynamics, advanced light microscopy, microfluidics, cell cycle research and organoid culture for the functional analysis of signalling dynamics in development and homeostasis. Somitogenesis in vertebrate embryos will be used to investigate the significance of signalling dynamics during embryogenesis. The small intestine will serve as a model of adult tissue homeostasis. By comparing these two model systems we will draw conclusions on the function of signalling dynamics in multicellular systems.

Objective

Tight coordination between proliferation and differentiation is key to proper development and homeostasis of multicellular systems. Cell-cell communication via signaling pathways has long been studied in this context. Encoding information in the temporal change of a signal, i.e. signaling dynamics, can ensure information transmission to be specific and accurate. Studies exemplifying the relevance of dynamic signaling raise the critical question: What is the function of signaling dynamics in controlling proliferation and differentiation at tissue level? My expertise in signaling dynamics, advanced light microscopy, microfluidics, development, cell cycle research and organoid culture provides a unique skill-set for the functional investigation of dynamic signaling during development and tissue homeostasis using two model systems:

Somitogenesis in vertebrate embryos is the sequential segmentation of growing tissue. It is controlled by signaling gradients and oscillations. Whereas differentiation has been studied extensively, it remains elusive (A) how cell proliferation is regulated and (B) whether there is a link between proliferation and signaling dynamics. Indeed, our preliminary data strongly indicate that cell proliferation impacts on signaling oscillations. Homeostasis of adult tissue is also maintained by signaling pathways balancing proliferation and differentiation. In the small intestine some of these pathways have recently been shown to be dynamic. We will apply a systematic approach to understand (A) are signaling pathways in the intestine dynamic and (B) what is the function. Our preliminary data support that combining organoid culture, light-sheet microscopy and microfluidic perturbation allows quantification and functional analysis of signaling dynamics.

By comparing signaling dynamics in development and homeostasis we will derive general principles of dynamic signal encoding in multicellular systems.

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Topic(s)

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ERC-STG - Starting Grant

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Call for proposal

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(opens in new window) ERC-2019-STG

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Host institution

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 500 000,00
Address
KLOVENIERSBURGWAL 29 HET TRIPPENHUIS
1011 JV AMSTERDAM
Netherlands

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Total cost

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€ 1 500 000,00

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