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Retinoic acid receptor γ activity plays a critical role in regulating early mouse gastruloid development
Olanipekun, Jide T. Edginton-White, Benjamin McQueen, Caitlin Brown, Geoffrey Johnson, William E. B.
Olanipekun, Jide T.
Edginton-White, Benjamin
McQueen, Caitlin
Brown, Geoffrey
Johnson, William E. B.
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2026-04-29
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Abstract
Regulation of all-trans retinoic acid (ATRA) signaling is crucial to early embryonic development. Embryonic stem (ES) cell-derived gastruloids mimic normal development in response to the Wnt/β-catenin agonist CHIR9901, and this study has examined the importance of the activities of RAR (retinoic acid receptor) α and γ to gastruloid development. Expression of retinoic acid receptor (RAR)γ within developing gastruloids was spatially restricted to primitive cells that co-expressed ES cell and early progenitor cell markers, i.e., Nanog, Sox2, and Oct4. In contrast, RARα expression was ubiquitous. mRNAs for the key enzymes involved in ATRA synthesis (Aldh1a2) and degradation (Cyp26a1) were not seen in cells that expressed RARγ. Treatment of ES cell-derived gastruloids with physiologically relevant (10 nM) levels of ATRA or with a highly selective RARγ agonist blocked normal developmental processes, preventing symmetry-breaking and axial elongation. This was not seen following treatments with an RARα agonist, where there was a tendency for enhanced axial elongation. Brachyury (TBXT) immuno-positive cells localized in the posterior end of elongated gastruloids in control- and RARα agonist-treated cultures, with Sox2 immuno-positive cells seen more widely, whilst both TBXT and Sox2 immuno-positive cells were randomly distributed throughout ATRA- and RARγ agonist-treated gastruloids. Concurrent treatment of gastruloids with 10 nM ATRA and 100 nM of an RARγ antagonist partially abrogated the ATRA-mediated block to axial elongation. Conversely, 10 nM RARγ antagonist treatments were associated with the formation of multi-axis gastruloid elongations, with comparatively little effect seen after treatments with an RARα antagonist. These findings reveal that RARγ plays a crucial role in the development of embryonic tissues.
Citation
Olanipekun, J. T., Edginton-White, B., McQueen, C., Brown, G., & Johnson, W. E. B. (2026). Retinoic acid receptor γ activity plays a critical role in regulating early mouse gastruloid development. International Journal of Molecular Sciences, 27(9), 3995. https://doi.org/10.3390/ijms27093995
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MDPI
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International Journal of Molecular Sciences
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Article
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en
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© 2026 by the authors. Licensee MDPI, Basel, Switzerland.
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1661-6596
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1422-0067
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W.E.B.J. was funded in this work by the University of Chester 2022/23 QR Fund grant no. 10M00037. G.B. was funded by UK Research and Innovation (UKRI) under the UK government’s Horizon Europe funding guarantee EP/Y030818/1 and is an associate partner to the EU-funded doctoral network eRaDicate.