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Cited by 300Developmental Biology and Gene RegulationPluripotent Stem Cells ResearchReproductive Biology and Fertility

Cell-to-cell expression variability followed by signal reinforcement progressively segregates early mouse lineages

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Ohnishi, Yusuke, Huber, Wolfgang, Tsumura, Akiko, Kang, Minjung, Xenopoulos, Panagiotis, Kurimoto, Kazuki, Oleś, Andrzej K., Araúzo-Bravo, Marcos J. +3 more·2014·Nature Cell Biology
DOI 10.1038/ncb2881PMC PMC4062977
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Abstract

It is now recognized that extensive expression heterogeneities among cells precede the emergence of lineages in the early mammalian embryo. To establish a map of pluripotent epiblast (EPI) versus primitive endoderm (PrE) lineage segregation within the inner cell mass (ICM) of the mouse blastocyst, we characterized the gene expression profiles of individual ICM cells. Clustering analysis of the transcriptomes of 66 cells demonstrated that initially they are non-distinguishable. Early in the segregation, lineage-specific marker expression exhibited no apparent correlation, and a hierarchical relationship was established only in the late blastocyst. Fgf4 exhibited a bimodal expression at the earliest stage analysed, and in its absence, the differentiation of PrE and EPI was halted, indicating that Fgf4 drives, and is required for, ICM lineage segregation. These data lead us to propose a model where stochastic cell-to-cell expression heterogeneity followed by signal reinforcement underlies ICM lineage segregation by antagonistically separating equivalent cells.

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  • These analyses provide precise ordering of markers during ICM lineage specification.

    “These analyses provide precise ordering of markers during ICM lineage specification (Extended Data Fig. 5c)3,22,28.”

    From The emergent landscape of the mouse gut endoderm at single-cell resolution (2019) · cites this paper as [28]

    The Results section (‘Progressive establishment of correlation’; page unavailable) reports an approximate activation hierarchy for seven PrE markers during the E3.5–E4.5 transition. It says evidence for a hierarchy was much weaker earlier, so it does not establish a precise ordering of markers throughout ICM lineage specification. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • FGF4 signaling is active across the ICM population and is critical for PrE specification.

    “While active across the ICM population25–27, FGF4 signaling is critical for PrE specification28,29.”

    From The emergent landscape of the mouse gut endoderm at single-cell resolution (2019) · cites this paper as [28]

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Authors
Ohnishi, Y., Huber, W., Tsumura, A., Kang, M., Xenopoulos, P., Kurimoto, K., Oleś, A. K., Araúzo-Bravo, M. J., Saitou, M., Hadjantonakis, A.-K., & Hiiragi, T.
Affiliations
  • European Molecular Biology Laboratory (DE)
  • Kyoto University (JP)
  • Max Planck Institute for Molecular Biomedicine (DE)
Corresponding author
Hiiragi, Takashi
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2013-12-01
Volume
16
Issue
1
Pages
27-37
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/ncb2881
PMC
PMC4062977
OpenAlex
W2072066100
Cited by
300
References
2
Citations by year
2026: 9 · 2025: 15 · 2024: 19 · 2023: 21 · 2022: 23 · 2021: 15 · 2020: 21 · 2019: 21 · 2018: 31 · 2017: 34 · 2016: 32 · 2015: 35 · 2014: 24
FWCI
13.60
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Japan Society for the Promotion of Science (24681039, 25650065)
  • National Cancer Institute (P30CA008748)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK084391)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD052115, NIH RO1-HD052115)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
Keywords
lineage segregation, inner cell mass, epiblast, primitive endoderm, FGF4, blastocyst, single-cell transcriptomics, stochastic differentiation, early mammalian embryo
MeSH terms
Animals, Cell Separation, Endoderm, Germ Layers, Models, Biological, Signal Transduction, Biomarkers, Polymerase Chain Reaction, Gene Expression Regulation, Developmental, Cell Lineage, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Principal Component Analysis, Mice, Fibroblast Growth Factor 4, Blastocyst Inner Cell Mass, Single-Cell Analysis

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