Article ; Online: Multi-layered regulation of neuroectoderm differentiation by retinoic acid in a primitive streak-like context.
2022 Volume 17, Issue 2, Page(s) 231–244
Abstract: The formation of the primitive streak (PS) and the subsequent induction of neuroectoderm are hallmarks of gastrulation. Combining an in vitro reconstitution of this process based on mouse embryonic stem cells (mESCs) with a collection of knockouts in ... ...
| Abstract | The formation of the primitive streak (PS) and the subsequent induction of neuroectoderm are hallmarks of gastrulation. Combining an in vitro reconstitution of this process based on mouse embryonic stem cells (mESCs) with a collection of knockouts in reporter mESC lines, we identified retinoic acid (RA) as a critical mediator of early neural induction triggered by TGFβ or Wnt signaling inhibition. Single-cell RNA sequencing analysis captured the temporal unfolding of cell type diversification, up to the emergence of somite and neural fates. In the absence of the RA-synthesizing enzyme Aldh1a2, a sensitive RA reporter revealed a hitherto unidentified residual RA signaling that specified neural fate. Genetic evidence showed that the RA-degrading enzyme Cyp26a1 protected PS-like cells from neural induction, even in the absence of TGFβ and Wnt antagonists. Overall, we characterized a multi-layered control of RA levels that regulates early neural differentiation in an in vitro PS-like system. |
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| MeSH term(s) | Aldehyde Dehydrogenase 1 Family/deficiency ; Aldehyde Dehydrogenase 1 Family/genetics ; Animals ; Benzamides/pharmacology ; Cell Differentiation/drug effects ; Dioxoles/pharmacology ; Ectoderm/cytology ; Ectoderm/metabolism ; Mice ; Mouse Embryonic Stem Cells/cytology ; Mouse Embryonic Stem Cells/drug effects ; Mouse Embryonic Stem Cells/metabolism ; Neurons/cytology ; Neurons/metabolism ; Primitive Streak/cytology ; Primitive Streak/metabolism ; Retinal Dehydrogenase/deficiency ; Retinal Dehydrogenase/genetics ; Retinoic Acid 4-Hydroxylase/metabolism ; Signal Transduction/drug effects ; Tretinoin/metabolism ; Tretinoin/pharmacology |
| Chemical Substances | 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide ; Benzamides ; Dioxoles ; Tretinoin (5688UTC01R) ; Cyp26a1 protein, mouse (EC 1.14.14.1) ; Retinoic Acid 4-Hydroxylase (EC 1.14.14.1) ; Aldehyde Dehydrogenase 1 Family (EC 1.2.1) ; Aldh1a2 protein, mouse (EC 1.2.1.36) ; Retinal Dehydrogenase (EC 1.2.1.36) |
| Language | English |
| Publishing date | 2022-01-20 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2720528-9 |
| ISSN | 2213-6711 ; 2213-6711 |
| ISSN (online) | 2213-6711 |
| ISSN | 2213-6711 |
| DOI | 10.1016/j.stemcr.2021.12.014 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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