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  Uncovering the role of RARɣ in mouse embryonic development using gastruloids


   Institute of Life Course and Medical Sciences

   Applications accepted all year round  Self-Funded PhD Students Only

About the Project

The three retinoic acid receptors (RAR), RARα, RARβ, RARɣ, are transcription factors that control gene expression and cell fate following their activation by all-trans retinoic acid (ATRA), the active metabolite of vitamin A. RARɣ for example, has been shown to be important for embryonic stem cell (ESC) differentiation, and during zebrafish development, RARɣ can block its development. Furthermore, in keeping with an importance to normal stem cell development, RARɣ is also an oncogene for many cancers.

To get a better understanding of how RARɣ controls ESC differentiation and consequently cell fate, we will take an innovative in vitro organoid approach using gastruloids as an experimental system. Gastruloids are 3D aggregates of mouse embryonic stem cells that mimic many embryonic patterning events in culture, and critically they develop all embryonic axes. The highly-controlled and scalable nature of gastruloids provides the means to access, observe and quantify the unfolding of early developmental patterning in detail.

In this project, we will examine the effect of chemically agonising and antagonising the action of RAR on gastruloid development and patterning, monitoring morphology and gene expression in fixed samples and in real-time. We take advantage of highly specific synthetic compounds that we have already developed and characterised. The student will be trained in state-of-the-art embryonic stem cell culture techniques (3D gastruloids), live-cell imaging, developmental biology, as well as cell and molecular biology techniques and analysis. 

Supervisors:

Dr David Turner;

Prof. Geoffrey Brown (University of Birmingham);

Biological Sciences (4)

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
Turner, D. A., et al. (2017) Anteroposterior polarity and elongation in the absence of extra-embryonic tissues and spatially localised signalling in gastruloids: mammalian embryonic organoids. Development;
Beccari L., et al. (2018) Multi-axial self-organisation properties in ES cell-derived murine Gastruloids. Nature
Veenvliet, J.V., et al. (2021) Sculpting with stem cells: how models of embryo development take shape. Development
Brown, G (2023). Targeting the retinoic acid pathway to eradicate cancer stem cells. International Journal of Molecular Sciences. 24, 2373.

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