De Mot Laurane, Gonze Didier, Bessonnard Sylvain, Chazaud Claire, Goldbeter Albert, Dupont Geneviève
Unité de Chronobiologie théorique, Faculté des Sciences, Université Libre de Bruxelles (ULB), Campus Plaine, Brussels, Belgium.
Laboratoire Génétique, Reproduction et Développement, Université Clermont Auvergne, Clermont-Ferrand, France; Institut National de la Santé et de la Recherche Médicale (INSERM), UMR1103, Clermont-Ferrand, France; Centre National de la Recherche Scientifique (CNRS), UMR6293, Clermont-Ferrand, France.
Biophys J. 2016 Feb 2;110(3):710-722. doi: 10.1016/j.bpj.2015.12.020.
During development, interactions between transcription factors control the specification of different cell fates. The regulatory networks of genetic interactions often exhibit multiple stable steady states; such multistability provides a common dynamical basis for differentiation. During early murine embryogenesis, cells from the inner cell mass (ICM) can be specified in epiblast (Epi) or primitive endoderm (PrE). Besides the intracellular gene regulatory network, specification is also controlled by intercellular interactions involving Erk signaling through extracellular Fgf4. We previously proposed a model that describes the gene regulatory network and its interaction with Erk signaling in ICM cells. The model displays tristability in a range of Fgf4 concentrations and accounts for the self-organized specification process observed in vivo. Here, we further investigate the origin of tristability in the model and analyze in more detail the specification process by resorting to a simplified two-cell model. We also carry out simulations of a population of 25 cells under various experimental conditions to compare their outcome with that of mutant embryos or of embryos submitted to exogenous treatments that interfere with Fgf signaling. The results are analyzed by means of bifurcation diagrams. Finally, the model predicts that heterogeneities in extracellular Fgf4 concentration play a primary role in the spatial arrangement of the Epi/PrE cells in a salt-and-pepper pattern. If, instead of heterogeneities in extracellular Fgf4 concentration, internal fluctuations in the levels of expression of the transcription factors are considered as a source of randomness, simulations predict the occurrence of unrealistic switches between the Epi and the PrE cell fates, as well as the evolution of some cells toward one of these states without passing through the previous ICM state, in contrast to what is observed in vivo.
在发育过程中，转录因子之间的相互作用控制着不同细胞命运的特化。基因相互作用的调控网络通常表现出多个稳定的稳态；这种多稳态为分化提供了一个共同的动力学基础。在小鼠早期胚胎发生过程中，内细胞团（ICM）的细胞可以分化为上胚层（Epi）或原始内胚层（PrE）。除了细胞内基因调控网络外，细胞特化还受细胞间相互作用的控制，这种相互作用涉及通过细胞外Fgf4的Erk信号传导。我们之前提出了一个模型，该模型描述了ICM细胞中的基因调控网络及其与Erk信号传导的相互作用。该模型在一系列Fgf4浓度范围内表现出三稳态，并解释了体内观察到的自组织特化过程。在这里，我们进一步研究该模型中三稳态的起源，并通过采用简化的双细胞模型更详细地分析特化过程。我们还在各种实验条件下对25个细胞的群体进行了模拟，以将其结果与突变胚胎或接受干扰Fgf信号传导的外源处理的胚胎的结果进行比较。通过分岔图对结果进行分析。最后，该模型预测细胞外Fgf4浓度的异质性在Epi/PrE细胞以椒盐模式的空间排列中起主要作用。相反，如果将转录因子表达水平的内部波动而非细胞外Fgf4浓度的异质性视为随机性的来源，模拟结果预测Epi和PrE细胞命运之间会出现不切实际的转换，以及一些细胞在未经过先前的ICM状态的情况下就朝着这些状态之一进化，这与体内观察到的情况相反。
