Four simple rules that are sufficient to generate the mammalian blastocyst – University of Copenhagen

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21 July 2017

Four simple rules that are sufficient to generate the mammalian blastocyst

Nissen, Silas Boye, Marta Perera, Javier Martin Gonzalez, Sophie M. Morgani, Mogens H. Jensen, Kim Sneppen, Joshua M. Brickman*, Ala Trusina* (2017). Four simple rules that are sufficient to generate the mammalian blastocyst. PLoS Biology; 15(7):e2000737, doi: 10.1371/journal.pbio.2000737. *joint corresponding authors



Early mammalian development is both highly regulative and self-organizing. It involves the interplay of cell position, predetermined gene regulatory networks, and environmental interactions to generate the physical arrangement of the blastocyst with precise timing. However, this process occurs in the absence of maternal information and in the presence of transcriptional stochasticity. How does the preimplantation embryo ensure robust, reproducible development in this context? It utilizes a versatile toolbox that includes complex intracellular networks coupled to cell—cell communication, segregation by differential adhesion, and apoptosis. Here, we ask whether a minimal set of developmental rules based on this toolbox is sufficient for successful blastocyst development, and to what extent these rules can explain mutant and experimental phenotypes. We implemented experimentally reported mechanisms for polarity, cell—cell signaling, adhesion, and apoptosis as a set of developmental rules in an agent-based in silico model of physically interacting cells. We find that this model quantitatively reproduces specific mutant phenotypes and provides an explanation for the emergence of heterogeneity without requiring any initial transcriptional variation. It also suggests that a fixed time point for the cells’ competence of fibroblast growth factor (FGF)/extracellular signal—regulated kinase (ERK) sets an embryonic clock that enables certain scaling phenomena, a concept that we evaluate quantitatively by manipulating embryos in vitro. Based on these observations, we conclude that the minimal set of rules enables the embryo to experiment with stochastic gene expression and could provide the robustness necessary for the evolutionary diversification of the preimplantation gene regulatory network.

Author summary

The first 4.5 days of mammalian embryo development proceeds without maternal information and is remarkably robust to perturbations. For example, if an early embryo is cut in half, it produces 2 perfectly patterned, smaller embryos. Where does the information guiding this development come from? Here, we explore this issue and ask whether a model composed of a simple set of rules governing cell behavior and cell—cell interactions produces in silico embryos. This agent-based computational model demonstrates that 4 rules, in which a cell makes decisions based on its neighbors to adopt polarity, make lineage choices, alter its adhesion, or die, can recapitulate blastocyst development in silico. By manipulating these rules, we could also recapitulate specific phenotypes at similar frequencies to those observed in vivo. One interesting prediction of our model is that the duration of cell—cell communication through fibroblast growth factor (FGF) signaling controls scaling of a region of the blastocyst, and we confirmed this experimentally. Taken together, our model specifies a set of rules that provide a framework for self-organization, and it is this self-organizing embryogenesis that may be an enabler of stochastic variation in evolution.