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Retinoic acid signaling is critical during the totipotency window in early mammalian development.
- Source :
-
Nature structural & molecular biology [Nat Struct Mol Biol] 2021 Jun; Vol. 28 (6), pp. 521-532. Date of Electronic Publication: 2021 May 27. - Publication Year :
- 2021
-
Abstract
- Totipotent cells hold enormous potential for regenerative medicine. Thus, the development of cellular models recapitulating totipotent-like features is of paramount importance. Cells resembling the totipotent cells of early embryos arise spontaneously in mouse embryonic stem (ES) cell cultures. Such '2-cell-like-cells' (2CLCs) recapitulate 2-cell-stage features and display expanded cell potential. Here, we used 2CLCs to perform a small-molecule screen to identify new pathways regulating the 2-cell-stage program. We identified retinoids as robust inducers of 2CLCs and the retinoic acid (RA)-signaling pathway as a key component of the regulatory circuitry of totipotent cells in embryos. Using single-cell RNA-seq, we reveal the transcriptional dynamics of 2CLC reprogramming and show that ES cells undergo distinct cellular trajectories in response to RA. Importantly, endogenous RA activity in early embryos is essential for zygotic genome activation and developmental progression. Overall, our data shed light on the gene regulatory networks controlling cellular plasticity and the totipotency program.
- Subjects :
- Acitretin pharmacology
Animals
Blastocyst Inner Cell Mass cytology
Cell Differentiation
Cells, Cultured
Dose-Response Relationship, Drug
Embryonic Stem Cells cytology
Embryonic Stem Cells drug effects
Female
Gene Regulatory Networks genetics
Genes, Reporter
Isotretinoin pharmacology
Male
Mice embryology
Mice, Inbred C57BL
Mice, Inbred CBA
Piperazines pharmacology
Pyrazoles pharmacology
RNA Interference
RNA, Messenger biosynthesis
RNA, Messenger genetics
RNA, Small Interfering pharmacology
RNA-Seq
Receptors, Retinoic Acid antagonists & inhibitors
Receptors, Retinoic Acid physiology
Signal Transduction drug effects
Totipotent Stem Cells drug effects
Transcription, Genetic
Tretinoin antagonists & inhibitors
Tretinoin pharmacology
Retinoic Acid Receptor gamma
Gene Expression Regulation, Developmental
Totipotent Stem Cells cytology
Tretinoin physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1545-9985
- Volume :
- 28
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Nature structural & molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 34045724
- Full Text :
- https://doi.org/10.1038/s41594-021-00590-w