Seminar by Silas Boye Nissen

Four Simple Rules that are Sufficient to Generate the Mammalian Blastocyst

Silas Boye Nissen, NBI

Early mammalian development is both highly regulative and self-organizing. It involves the interplay of cell position, pre-determined 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 pre-implantation embryo en- sure robust, reproducible development in this context? It utilizes a versatile toolbox that includes complex intracellular networks coupled by cell-cell communication, segregation by differential adhesion, and apoptosis. Here, we ask whether this minimal set of developmental rules 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 initial transcriptional variation. It also suggests that a fixed time point for FGF/ERK competence sets the embryonic clock that enables scaling phenomena. A minimal set of cell based rules enables the embryo to experiment with stochastic gene expression and could provide the robustness necessary for the evolutionary diversification of the pre-implantation gene regulatory network.