About the Project
Gastrulation is a pivotal stage in development where an initially uniform mass of cells transforms into an organised structure with distinct cell types arranged along the three body axes. This process depends on a small, evolutionarily conserved set of signalling pathways that guide cell fate decisions. Among these, Wnt and Notch signalling play crucial but often opposing roles. Evidence suggests they are part of an integrated network that balances alternative fates, yet how they coordinate to…
drive correct outcomes during gastrulation remains unclear. Most work has focussed on Notch’s transcriptional role, while its non-transcriptional function in attenuating Wnt signalling by modulating β-Catenin has received little attention.
Background: Gastrulation is a pivotal stage in development where an initially uniform mass of cells transforms into an organised structure with distinct cell types arranged along the three body axes. This process depends on a small, evolutionarily conserved set of signalling pathways that guide cell fate decisions. Among these, Wnt and Notch signalling play crucial but often opposing roles. Evidence suggests they are part of an integrated network that balances alternative fates, yet how they coordinate to drive correct outcomes during gastrulation remains unclear. Most work has focussed on Notch’s transcriptional role, while its non-transcriptional function in attenuating Wnt signalling by modulating β-Catenin has received little attention.
Objectives: This project will examine the hypothesis that Notch signalling acts as a molecular attenuator of Wnt signalling, using our state-of-the-art 3D gastruloid model system. We will:
- Define which developmental processes (e.g. symmetry breaking, axis formation, elongation, morphogenesis) are governed by transcriptional versus non-transcriptional Notch signalling.
- Examine how non-canonical Notch signalling attenuates of Wnt/β-Catenin signalling on gastruloid development and patterning;
- Investigate how cells interpret the dynamics of Wnt and Notch signalling to make final fate decisions.
Experimental Approach: The student will combine our 3D gastruloid model with high-content imaging and live fluorescent reporters of axial markers. This will be coupled with chemical inhibitors of Notch and genetic perturbations using our newly generated Notch mutant lines. Gastruloids, 3D aggregates of embryonic stem cells develop an organised post-occipital pattern of gene expression in a spatially- and temporally-coordinated manner, mimicking many early embryonic patterning events. They develop all three embryonic axes allowing detailed examination of signalling inputs and processes required to specify cell fate and morphogenesis without using embryos.
Novelty: Our 3D gastruloid approach is radically different to traditional in vivo model systems, allowing us to spearhead a new understanding of how integrated Notch and signalling control key developmental processes. The minimal nature of the model system allows us to ask fundamental questions about what cells can do (and how signals direct their fate) that would be impossible to do in embryo due to technical reasons.
Student Development and Training: The student will benefit from co-supervision from the primary and secondary supervisors, gaining training in developmental signalling, 3D gastruloid culture, stem cell biology, advanced imaging, and biochemical approaches. Regular supervisory meetings and integration across the two groups will provide robust support, while day-to-day guidance will come from postdocs and peers. Both supervisors have proven records of mentoring early-career researchers and supporting colleagues into diverse scientific and non-scientific career paths. The student will be encouraged to participate in DiMeN training, present at international meetings, and engage with the supervisors’ collaborative networks. This will ensure they develop independence, technical versatility, and a competitive skill set for careers in academia, industry, or translational research.
The successful student will gain access to cutting-edge 3D stem cell models, quantitative imaging, and biochemical analysis, developing a highly transferrable interdisciplinary expertise.
Supervisory team:
- Primary Supervisor: David Turner
- www.gastruloids.com
- https://www.liverpool.ac.uk/people/david-turner
- Secondary Supervisor: David Wilkinson
- https://www.liverpool.ac.uk/people/david-john-wilkinson
Please email your CV and cover letter to the primary supervisor, Dr David Turner, in the first instance david.turner@liverpool.ac.uk
References
- van den Brink, S. C., et al. (2014). "Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells." Development 141(22): 4231-4242.
- Beccari, L., et al. (2018). "Multi-axial self-organization properties of mouse embryonic stem cells into gastruloids." Nature 562(7726): 272-276.
- Turner, D. A., et al. (2017). "Anteroposterior polarity and elongation in the absence of extra-embryonic tissues and of spatially localised signalling in gastruloids: mammalian embryonic organoids." Development 144(21): 3894-3906.
- Turner, D. A. and A. Martinez Arias (2024). "Three-dimensional stem cell models of mammalian gastrulation." Bioessays: e2400123.
- Munoz Descalzo, S. and A. Martinez Arias (2012). "The structure of Wntch signalling and the resolution of transition states in development." Semin Cell Dev Biol 23(4): 443-449.
- Hayward, P., et al. (2008). "Wnt/Notch signalling and information processing during development." Development 135(3): 411-424.
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