Abstract
During mammalian blastocyst development, inner cell mass (ICM) cells differentiate into epiblast (Epi) or primitive endoderm (PrE). These two fates are characterized by the expression of the transcription factors NANOG and GATA6, respectively. Here, we investigate the spatio-temporal distribution of NANOG and GATA6 expressing cells in the ICM of the mouse blastocysts with quantitative three-dimensional single cell-based neighbourhood analyses. We define the cell neighbourhood by local features, which include the expression levels of both fate markers expressed in each cell and its neighbours, and the number of neighbouring cells. We further include the position of a cell relative to the centre of the ICM as a global positional feature. Our analyses reveal a local three-dimensional pattern that is already present in early blastocysts: 1) Cells expressing the highest NANOG levels are surrounded by approximately nine neighbours, while 2) cells expressing GATA6 cluster according to their GATA6 levels. This local pattern evolves into a global pattern in the ICM that starts to emerge in mid blastocysts. We show that FGF/MAPK signalling is involved in the three-dimensional distribution of the cells and, using a mutant background, we further show that the GATA6 neighbourhood is regulated by NANOG. Our quantitative study suggests that the three-dimensional cell neighbourhood plays a role in Epi and PrE precursor specification. Our results highlight the importance of analysing the three-dimensional cell neighbourhood while investigating cell fate decisions during early mouse embryonic development.
| Original language | English |
|---|---|
| Article number | e0233030 |
| Journal | PLoS ONE |
| Volume | 15 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 2020 |
Bibliographical note
Funding Information:Research in the AK Stelzer is supported by the Deutsche Forschungsgemeinschaft (DFG, CEF-MC II, EXC-115). Research in the Mu?oz-Descalzo lab (in Bath) was supported by the University of Bath and a Wellcome Trust Seed Award (109589/Z/15/Z). Research in the Mu?oz-Descalzo lab (in Las Palmas) is supported by the ?Viera y Clavijo? Program from the ACIISI and the ULPGC. JL (in Las Palmas) is supported by the Cabildo de Gran Canaria and the ULPGC. SCF and SMD acknowledge the support by an International Exchanges Grant from The Royal Society (IE141022). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Christian Schr?ter, Jennifer Nichols, Joaqu?n de Navascu?s and Alfonso Mart?nez-Arias for helpful comments and Carl-Magnus Svensson for critical reading of the manuscript. We also want to thank N?stor S?iz and Kat Hadjantonakis for their comments, sharing their quantitative data through GitHub as well as through personal communication. We also want to thank Claire Chazaud for kindly sharing Nanog heterozygous mice. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2020 Fischer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
Funding
Research in the AK Stelzer is supported by the Deutsche Forschungsgemeinschaft (DFG, CEF-MC II, EXC-115). Research in the Mu?oz-Descalzo lab (in Bath) was supported by the University of Bath and a Wellcome Trust Seed Award (109589/Z/15/Z). Research in the Mu?oz-Descalzo lab (in Las Palmas) is supported by the ?Viera y Clavijo? Program from the ACIISI and the ULPGC. JL (in Las Palmas) is supported by the Cabildo de Gran Canaria and the ULPGC. SCF and SMD acknowledge the support by an International Exchanges Grant from The Royal Society (IE141022). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Christian Schr?ter, Jennifer Nichols, Joaqu?n de Navascu?s and Alfonso Mart?nez-Arias for helpful comments and Carl-Magnus Svensson for critical reading of the manuscript. We also want to thank N?stor S?iz and Kat Hadjantonakis for their comments, sharing their quantitative data through GitHub as well as through personal communication. We also want to thank Claire Chazaud for kindly sharing Nanog heterozygous mice. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
ASJC Scopus subject areas
- General Biochemistry,Genetics and Molecular Biology
- General Agricultural and Biological Sciences
- General