title: Gata6, Nanog and Erk signaling control cell fate in the inner cell mass through a tristable regulatory network.
abstract: During blastocyst formation, inner cell mass (ICM) cells differentiate into either epiblast (Epi) or primitive endoderm (PrE) cells, labeled by Nanog and Gata6, respectively, and organized in a salt-and-pepper pattern. Previous work in the mouse has shown that, in absence of Nanog, all ICM cells adopt a PrE identity. Moreover, the activation or the blockade of the Fgf/RTK pathway biases cell fate specification towards either PrE or Epi, respectively. We show that, in absence of Gata6, all ICM cells adopt an Epi identity. Furthermore, the analysis of Gata6(+/-) embryos reveals a dose-sensitive phenotype, with fewer PrE-specified cells. These results and previous findings have enabled the development of a mathematical model for the dynamics of the regulatory network that controls ICM differentiation into Epi or PrE cells. The model describes the temporal dynamics of Erk signaling and of the concentrations of Nanog, Gata6, secreted Fgf4 and Fgf receptor 2. The model is able to recapitulate most of the cell behaviors observed in different experimental conditions and provides a unifying mechanism for the dynamics of these developmental transitions. The mechanism relies on the co-existence between three stable steady states (tristability), which correspond to ICM, Epi and PrE cells, respectively. Altogether, modeling and experimental results uncover novel features of ICM cell fate specification such as the role of the initial induction of a subset of cells into Epi in the initiation of the salt-and-pepper pattern, or the precocious Epi specification in Gata6(+/-) embryos.
authors.affiliation: Clermont Université, Université d'Auvergne, Laboratoire GReD, Clermont-Ferrand F-63000, France Inserm, UMR1103, Clermont-Ferrand F-63001, France CNRS, UMR6293, Clermont-Ferrand F-63001, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bessonnard
authors.affiliation: Unité de Chronobiologie théorique, Faculté des Sciences, Université Libre de Bruxelles (ULB), Campus Plaine, CP 231, Brussels B-1050, Belgium.
authors.forename: Laurane
authors.initials: L
authors.lastname: De Mot
authors.affiliation: Unité de Chronobiologie théorique, Faculté des Sciences, Université Libre de Bruxelles (ULB), Campus Plaine, CP 231, Brussels B-1050, Belgium.
authors.forename: Didier
authors.initials: D
authors.lastname: Gonze
authors.affiliation: Clermont Université, Université d'Auvergne, Laboratoire GReD, Clermont-Ferrand F-63000, France Inserm, UMR1103, Clermont-Ferrand F-63001, France CNRS, UMR6293, Clermont-Ferrand F-63001, France.
authors.forename: Manon
authors.initials: M
authors.lastname: Barriol
authors.affiliation: Clermont Université, Université d'Auvergne, Laboratoire GReD, Clermont-Ferrand F-63000, France Inserm, UMR1103, Clermont-Ferrand F-63001, France CNRS, UMR6293, Clermont-Ferrand F-63001, France.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Dennis
authors.affiliation: Unité de Chronobiologie théorique, Faculté des Sciences, Université Libre de Bruxelles (ULB), Campus Plaine, CP 231, Brussels B-1050, Belgium Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Center at Stellenbosch University, Stellenbosch 7600, South Africa.
authors.forename: Albert
authors.initials: A
authors.lastname: Goldbeter
authors.affiliation: Unité de Chronobiologie théorique, Faculté des Sciences, Université Libre de Bruxelles (ULB), Campus Plaine, CP 231, Brussels B-1050, Belgium genevieve.dupont@ulb.ac.be claire.chazaud@udamail.fr.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Dupont
authors.affiliation: Clermont Université, Université d'Auvergne, Laboratoire GReD, Clermont-Ferrand F-63000, France Inserm, UMR1103, Clermont-Ferrand F-63001, France CNRS, UMR6293, Clermont-Ferrand F-63001, France genevieve.dupont@ulb.ac.be claire.chazaud@udamail.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Chazaud
mesh_terms: D000818:Animals; D053624:Blastocyst Inner Cell Mass / Q000166:cytology*; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology*; D004707:Endoderm / Q000166:cytology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D050993:GATA6 Transcription Factor / Q000378:metabolism*; D053263:Gene Regulatory Networks / Q000502:physiology*; D005855:Germ Layers / Q000166:cytology; D018398:Homeodomain Proteins / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D007211:Indoles; D051379:Mice; D018613:Microscopy, Confocal; D008954:Models, Biological; D000071317:Nanog Homeobox Protein; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D018709:Statistics, Nonparametric
chemical_list: D050993:GATA6 Transcription Factor; C494760:Gata6 protein, mouse; D018398:Homeodomain Proteins; D007211:Indoles; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; C007293:DAPI; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Bifurcation; Cell lineage specification; Epiblast; Gata6 mutants; Mathematical model; Mouse; Multistability; Preimplantation; Primitive endoderm