Negative feedback on Retinoic Acid by Brachyury guides gastruloid symmetry-breaking

Hennessy, Meagan J, Fulton, Timothy ORCID: 0000-0002-0386-1821, Turner, David A ORCID: 0000-0002-3447-7662 and Steventon, Ben ORCID: 0000-0001-7838-839X
(2023) Negative feedback on Retinoic Acid by Brachyury guides gastruloid symmetry-breaking. [Preprint]

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<jats:title>Abstract</jats:title><jats:p>Establishment of the vertebrate body plan requires a combination of extra-embryonic signalling to establish morphogen gradients, and an underlying self-assembly mechanism that contributes to pattern regulation and robustness. Gastruloids are aggregates of mouse embryonic stem cells that break morphological symmetry and polarise<jats:italic>Brachyury</jats:italic>(<jats:italic>Bra</jats:italic>) expression in the absence of extra-embryonic signals. However, the mechanism by which symmetry breaking occurs is not yet known. During gastrulation and body axis elongation, retinoic acid (RA) and<jats:italic>Cyp26a1</jats:italic>are polarised along the anteroposterior axis, and this is critical for balancing the decision of cells to self-renew or differentiate. We found that symmetry-breaking in gastruloids is coincident with the separation of<jats:italic>Aldh1a2</jats:italic>and<jats:italic>Cyp26a1</jats:italic>expression, and that feedback from<jats:italic>Bra</jats:italic>is critical for maintaining polarised<jats:italic>Cyp26a1</jats:italic>gene expression in the gastruloid posterior region. Furthermore, we reveal a short temporal window where RA signalling can negatively influence both<jats:italic>Bra</jats:italic>and<jats:italic>Cyp26a1</jats:italic>expression. These observations lead us to suggest a mechanism of how initial gastruloid patterning, subsequent elongation, and evolving network topologies can create defined boundaries of RA signalling that permits proper axial patterning and gastruloid growth.</jats:p>

Item Type: Preprint
Uncontrolled Keywords: Stem Cell Research, 1 Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences
Depositing User: Symplectic Admin
Date Deposited: 06 Jun 2023 07:35
Last Modified: 07 Jun 2024 11:00
DOI: 10.1101/2023.06.02.543388
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