Transitions in cell potency during early mouse development are driven by Notch
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Spain
- Sloan Kettering Institute, United States
Abstract
The Notch signalling pathway plays fundamental roles in diverse developmental processes in metazoans, where it is important in driving cell fate and directing differentiation of various cell types. However, we still have limited knowledge about the role of Notch in early preimplantation stages of mammalian development, or how it interacts with other signalling pathways active at these stages such as Hippo. By using genetic and pharmacological tools in vivo, together with image analysis of single embryos and pluripotent cell culture, we have found that Notch is active from the 4-cell stage. Transcriptomic analysis in single morula identified novel Notch targets, such as early naïve pluripotency markers or transcriptional repressors such as TLE4. Our results reveal a previously undescribed role for Notch in driving transitions during the gradual loss of potency that takes place in the early mouse embryo prior to the first lineage decisions.
Data availability
Sequencing data have been deposited in GEO under accession code GSE121979.
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Transitions in cell potency during early mouse development are driven by NotchNCBI Gene Expression Omnibus, GSE121979.
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The landscape of accessible chromatin in mammalian pre-implantation embryosNCBI Gene Expression Omnibus, GSE66390.
Article and author information
Author details
Anna-Katerina Hadjantonakis
Funding
Ministerio de Economía y Competitividad (BFU2017-84914-P)
- Sergio Menchero
- Isabel Rollan
- Antonio Lopez-Izquierdo
- Maria Jose Andreu
- Julio Sainz de Aja
- Javier Adan
- Teresa Rayon
- Miguel Manzanares
ProCNIC Foundation
- Sergio Menchero
- Isabel Rollan
- Antonio Lopez-Izquierdo
- Maria Jose Andreu
- Julio Sainz de Aja
- Javier Adan
- Rui Benedito
- Teresa Rayon
- Miguel Manzanares
National Institutes of Health (NIH-R01DK084391)
- Minjung Kang
- Anna-Katerina Hadjantonakis
Ministerio de Economía y Competitividad (BFU2015-72319-EXP)
- Sergio Menchero
- Isabel Rollan
- Maria Jose Andreu
- Miguel Manzanares
Ministerio de Economía y Competitividad (SEV-2015-0505)
- Sergio Menchero
- Isabel Rollan
- Antonio Lopez-Izquierdo
- Maria Jose Andreu
- Julio Sainz de Aja
- Javier Adan
- Rui Benedito
- Teresa Rayon
- Miguel Manzanares
Ministerio de Economía y Competitividad (SVP-2013-067930)
- Sergio Menchero
National Institutes of Health (NIH-R01HD094868)
- Minjung Kang
- Anna-Katerina Hadjantonakis
National Institutes of Health (NIH-P30CA008748)
- Minjung Kang
- Anna-Katerina Hadjantonakis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Elizabeth Robertson, University of Oxford, United Kingdom
Ethics
Animal experimentation: This study was performed in strict accordance with national and European Legislation. Procedures were approved by the CNIC Animal Welfare Ethics Committee and by the Area of Animal Protection of the Regional Government of Madrid (ref. PROEX 196/14).
Version history
- Received: October 17, 2018
- Accepted: April 7, 2019
- Accepted Manuscript published: April 8, 2019 (version 1)
- Version of Record published: April 26, 2019 (version 2)
Copyright
© 2019, Menchero et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Transitions in cell potency during early mouse development are driven by Notch
eLife 8:e42930.
https://doi.org/10.7554/eLife.42930
Further reading
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- Chromosomes and Gene Expression
Splicing is the stepwise molecular process by which introns are removed from pre-mRNA and exons are joined together to form mature mRNA sequences. The ordering and spatial distribution of these steps remain controversial, with opposing models suggesting splicing occurs either during or after transcription. We used single-molecule RNA FISH, expansion microscopy, and live-cell imaging to reveal the spatiotemporal distribution of nascent transcripts in mammalian cells. At super-resolution levels, we found that pre-mRNA formed clouds around the transcription site. These clouds indicate the existence of a transcription-site-proximal zone through which RNA move more slowly than in the nucleoplasm. Full-length pre-mRNA undergo continuous splicing as they move through this zone following transcription, suggesting a model in which splicing can occur post-transcriptionally but still within the proximity of the transcription site, thus seeming co-transcriptional by most assays. These results may unify conflicting reports of co-transcriptional versus post-transcriptional splicing.
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- Chromosomes and Gene Expression
- Genetics and Genomics
Heterogeneity in endothelial cell (EC) sub-phenotypes is becoming increasingly appreciated in atherosclerosis progression. Still, studies quantifying EC heterogeneity across whole transcriptomes and epigenomes in both in vitro and in vivo models are lacking. Multiomic profiling concurrently measuring transcriptomes and accessible chromatin in the same single cells was performed on six distinct primary cultures of human aortic ECs (HAECs) exposed to activating environments characteristic of the atherosclerotic microenvironment in vitro. Meta-analysis of single-cell transcriptomes across 17 human ex vivo arterial specimens was performed and two computational approaches quantitatively evaluated the similarity in molecular profiles between heterogeneous in vitro and ex vivo cell profiles. HAEC cultures were reproducibly populated by four major clusters with distinct pathway enrichment profiles and modest heterogeneous responses: EC1-angiogenic, EC2-proliferative, EC3-activated/mesenchymal-like, and EC4-mesenchymal. Quantitative comparisons between in vitro and ex vivo transcriptomes confirmed EC1 and EC2 as most canonically EC-like, and EC4 as most mesenchymal with minimal effects elicited by siERG and IL1B. Lastly, accessible chromatin regions unique to EC2 and EC4 were most enriched for coronary artery disease (CAD)-associated single-nucleotide polymorphisms from Genome Wide Association Studies (GWAS), suggesting that these cell phenotypes harbor CAD-modulating mechanisms. Primary EC cultures contain markedly heterogeneous cell subtypes defined by their molecular profiles. Surprisingly, the perturbations used here only modestly shifted cells between subpopulations, suggesting relatively stable molecular phenotypes in culture. Identifying consistently heterogeneous EC subpopulations between in vitro and ex vivo models should pave the way for improving in vitro systems while enabling the mechanisms governing heterogeneous cell state decisions.
