Abstract

Embryonic development is a self-organised process during which cells divide, interact, change fate according to a complex gene regulatory network and organise themselves in a three-dimensional space. Here, we model this complex dynamic phenomenon in the context of the acquisition of epiblast and primitive endoderm identities within the inner cell mass of the preimplantation embryo in the mouse. The multiscale model describes cell division and interactions between cells, as well as biochemical reactions inside each individual cell and in the extracellular matrix. The computational results first confirm that the previously proposed mechanism by which extra-cellular signalling allows cells to select the appropriate fate in a tristable regulatory network is robust when considering a realistic framework involving cell division and three-dimensional interactions. The simulations recapitulate a variety of in vivo observations on wild-type and mutant embryos and suggest that the gene regulatory network confers differential plasticity to the different cell fates. A detailed analysis of the specification process emphasizes that developmental transitions and the salt-and-pepper patterning of epiblast and primitive endoderm cells from a homogenous population of inner cell mass cells arise from the interplay between the internal gene regulatory network and extracellular signalling by Fgf4. Importantly, noise is necessary to create some initial heterogeneity in the specification process. The simulations suggest that initial cell-to-cell differences originating from slight inhomogeneities in extracellular Fgf4 signalling, in possible combination with slightly different concentrations of the key transcription factors between daughter cells, are able to break the original symmetry and are amplified in a flexible and self-regulated manner until the blastocyst stage.

Highlights

  • The development of the single mammalian cell zygote into an embryo arises through the combined effect of cell divisions and differentiations

  • In a model devoted to the analysis of the specification of Epi and primitive endoderm (PrE) cells from inner cell mass (ICM) cells in which Nanog and Gata[6] expressions are controlled by both auto-activation and cross-inhibition, we showed that tristability can arise from the interplay between Fgf[4] and the Nanog-Gata[6] regulations

  • Specification of Epi and PrE cells arranged in a 3D salt-and pepper pattern The simulations of the specification of ICM cells into Epi or PrE cells in a 3D framework, taking into account divisions and both npj Systems Biology and Applications (2017) 16 proveniences of ICM cells, show that the proposed gene regulatory network (GRN) is able to giving rise to a mixed population of Epi and PrE cells

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Summary

Introduction

The development of the single mammalian cell zygote into an embryo arises through the combined effect of cell divisions and differentiations.

Results
Conclusion
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