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.

早期的哺乳动物发育既具有高度调节性又具有自组织性。它涉及细胞位置，预定的基因调控网络和环境相互作用之间的相互作用，以精确的时间生成胚泡的物理排列。但是，此过程发生在没有母体信息和转录随机性的情况下。在这种情况下，植入前胚胎如何确保稳健，可复制的发育？它利用了一个多功能的工具箱，该工具箱包括耦合到细胞间通信，通过差异粘附分离和凋亡的复杂细胞内网络。在这里，我们询问基于此工具箱的最小开发规则集是否足以成功地囊胚发育，以及这些规则在多大程度上可以解释突变体和实验表型。在基于代理的物理相互作用细胞计算机模型中，我们实施了极性，细胞间信号传导，粘附和凋亡的实验性报告机制，作为一组发展规则。我们发现该模型定量地重现特定的突变表型，并为不需要任何初始转录变异的异质性的出现提供了解释。这也表明，成纤维细胞生长因子（FGF）/细胞外信号调节激酶（ERK）的细胞功能的固定时间点设置了能够实现某些缩放现象的胚胎钟，我们通过在体外操作胚胎来定量评估这一概念。 。基于这些观察，