Transitions in cell potency during early mouse development are driven by Notch
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.
-
Transitions in cell potency during early mouse development are driven by NotchNCBI Gene Expression Omnibus, GSE121979.
-
The landscape of accessible chromatin in mammalian pre-implantation embryosNCBI Gene Expression Omnibus, GSE66390.
Article and author information
Author details
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.
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).
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.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Chromosomes and Gene Expression
RNA interference (RNAi) is a conserved pathway that utilizes Argonaute proteins and their associated small RNAs to exert gene regulatory function on complementary transcripts. While the majority of germline-expressed RNAi proteins reside in perinuclear germ granules, it is unknown whether and how RNAi pathways are spatially organized in other cell types. Here, we find that the small RNA biogenesis machinery is spatially and temporally organized during Caenorhabditis elegans embryogenesis. Specifically, the RNAi factor, SIMR-1, forms visible concentrates during mid-embryogenesis that contain an RNA-dependent RNA polymerase, a poly-UG polymerase, and the unloaded nuclear Argonaute protein, NRDE-3. Curiously, coincident with the appearance of the SIMR granules, the small RNAs bound to NRDE-3 switch from predominantly CSR-class 22G-RNAs to ERGO-dependent 22G-RNAs. NRDE-3 binds ERGO-dependent 22G-RNAs in the somatic cells of larvae and adults to silence ERGO-target genes; here we further demonstrate that NRDE-3-bound, CSR-class 22G-RNAs repress transcription in oocytes. Thus, our study defines two separable roles for NRDE-3, targeting germline-expressed genes during oogenesis to promote global transcriptional repression, and switching during embryogenesis to repress recently duplicated genes and retrotransposons in somatic cells, highlighting the plasticity of Argonaute proteins and the need for more precise temporal characterization of Argonaute-small RNA interactions.
-
- Chromosomes and Gene Expression
- Genetics and Genomics
A new method for mapping torsion provides insights into the ways that the genome responds to the torsion generated by RNA polymerase II.