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Interactions between Nodal and Wnt signalling Drive Robust Symmetry-Breaking and Axial Organisation in Gastruloids (Embryonic Organoids)

View ORCID ProfileD.A. Turner, C.R. Glodowski, L. Alonso-Crisostomo, View ORCID ProfileP. Baillie-Johnson, P.C. Hayward, J. Collignon, C. Gustavsen, P. Serup, C. Schröter, A. Martinez Arias
doi: https://doi.org/10.1101/051722
D.A. Turner
1Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, United Kingdom
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  • For correspondence: ama11@cam.ac.uk dat40@cam.ac.uk
C.R. Glodowski
1Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, United Kingdom
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L. Alonso-Crisostomo
1Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, United Kingdom
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P. Baillie-Johnson
1Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, United Kingdom
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P.C. Hayward
1Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, United Kingdom
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J. Collignon
2Universit Paris-Diderot, CNRS, Institut Jacques Monod, UMR 7592, Development and Neurobiology Programme, F-75013 Paris, France
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C. Gustavsen
3Danish Stem Cell Center, University of Copenhagen, DK-2200 Copenhagen, Denmark
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P. Serup
3Danish Stem Cell Center, University of Copenhagen, DK-2200 Copenhagen, Denmark
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C. Schröter
1Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, United Kingdom
4Max Planck Institute of Molecular Physiology, Dortmund, Germany
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A. Martinez Arias
1Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, United Kingdom
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  • For correspondence: ama11@cam.ac.uk dat40@cam.ac.uk
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Abstract

Generation of asymmetry within the early embryo is a critical step in the establishment of the three body axes, providing a reference for the patterning of the organism. To study the establishment of asymmetry and the development of the anteroposterior axis (AP) in culture, we utilised our ‘Gastruloid’ model system. ‘Gastruloids’, highly reproducible embryonic organoids formed from aggregates of mouse embryonic stem cells, display symmetry-breaking, polarised gene expression and axial development, mirroring the processes on a time-scale similar to that of the mouse embyro. Using Gastruloids formed from mouse ESCs containing reporters for Wnt, FGF and Nodal signalling, we were able to quantitatively assess the contribution of these signalling pathways to the establishment of asymmetry through single time-point and live-cell fluorescence microscopy.

During the first 24-48h of culture, interactions between the Wnt/β-Catenin and Nodal/TGF/β signalling pathways promote the initial symmetry-breaking event, manifested through polarised Brachyury (T/Bra) expression. Neither BMP nor FGF signalling is required for the establishment of asymmetry, however Wnt signalling is essential for the amplification and stability of the initial patterning event. Additionally, low, endogenous levels of FGF (24-48h) has a role in the amplification of the established pattern at later time-points.

Our results confirm that Gastruloids behave like epiblast cells in the embryo, leading us to translate the processes and signalling involved in pattern formation of Gastruloids in culture to the development of the embryo, firmly establishing Gastruloids as a highly reproducible, robust model system for studying cell fate decisions and early pattern formation in culture.

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Posted May 13, 2016.
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Interactions between Nodal and Wnt signalling Drive Robust Symmetry-Breaking and Axial Organisation in Gastruloids (Embryonic Organoids)
D.A. Turner, C.R. Glodowski, L. Alonso-Crisostomo, P. Baillie-Johnson, P.C. Hayward, J. Collignon, C. Gustavsen, P. Serup, C. Schröter, A. Martinez Arias
bioRxiv 051722; doi: https://doi.org/10.1101/051722
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Interactions between Nodal and Wnt signalling Drive Robust Symmetry-Breaking and Axial Organisation in Gastruloids (Embryonic Organoids)
D.A. Turner, C.R. Glodowski, L. Alonso-Crisostomo, P. Baillie-Johnson, P.C. Hayward, J. Collignon, C. Gustavsen, P. Serup, C. Schröter, A. Martinez Arias
bioRxiv 051722; doi: https://doi.org/10.1101/051722

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