title: Cell-to-cell expression variability followed by signal reinforcement progressively segregates early mouse lineages.
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.
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohnishi
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Wolfgang
authors.identifier: 0000000204742218
authors.initials: W
authors.lastname: Huber
authors.affiliation: Institute for Integrated Cell-Material Sciences, Kyoto University, Yoshida-Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Tsumura
authors.affiliation: Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, Box 371, New York, New York 10065, USA.
authors.forename: Minjung
authors.initials: M
authors.lastname: Kang
authors.affiliation: Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, Box 371, New York, New York 10065, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Xenopoulos
authors.affiliation: 1] Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [2] JST, ERATO, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kurimoto
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Andrzej K
authors.initials: AK
authors.lastname: Oleś
authors.affiliation: Computational Biology and Bioinformatics Group, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
authors.forename: Marcos J
authors.initials: MJ
authors.lastname: Araúzo-Bravo
authors.affiliation: 1] Institute for Integrated Cell-Material Sciences, Kyoto University, Yoshida-Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan [2] Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [3] JST, ERATO, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [4] Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin Yoshida, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Mitinori
authors.initials: M
authors.lastname: Saitou
authors.affiliation: Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, Box 371, New York, New York 10065, USA.
authors.forename: Anna-Katerina
authors.initials: AK
authors.lastname: Hadjantonakis
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hiiragi
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D053624:Blastocyst Inner Cell Mass / Q000166:cytology / Q000378:metabolism; D019070:Cell Lineage / Q000187:drug effects*; D002469:Cell Separation; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D051519:Fibroblast Growth Factor 4 / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005855:Germ Layers / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D025341:Principal Component Analysis; D015398:Signal Transduction / Q000235:genetics; D059010:Single-Cell Analysis
chemical_list: D015415:Biomarkers; C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4