Stochasticity and cell fate decision in the early mammalian embryo
Geneviève Dupont
Unité de Chronobiologie Théorique
Université Libre de Bruxelles (ULB)
Brussels, Belgium
How a cell's identity is established and maintained is a central question in developmental biology. Cell fate acquisition is governed by gene regulatory networks (GRN), which are often modulated by cellular signalling. A well-characterized example is that of the establishment of Epiblast (Epi) and Primitive Endoderm (PrE) identities within the Inner Cell Mass (ICM) of the mammalian embryo at the blastocyst stage. This differentiation is asynchronous and leads to an apparently random distribution, visualized by the mutually exclusive expression of markers such as NANOG (Epi) and GATA6 (PrE) that characterizes the "salt and pepper" pattern. This network is under the control of extracellular FGF4.
A minimal model formalizing this signalling controlled GRN exhibits tristability in a specific range of FGF4 concentration, with each stable steady state displaying the characteristics of one of the observed cell fates (ICM, Epi or PrE). Simulations of cell populations account for the emergence of the salt and pepper pattern of Epi and PrE cells when considering some source of heterogeneity in the individual GRN. Internal fluctuations or slight variations in the values of the parameters of the model are indeed required to initiate differentiation among the population of first arising ICM cells. The nature of this source of noise is experimentally unknown. A statistical analysis of the outcomes of simulations performed with different assumptions regarding the source of noise allows to suggest likely cell-to-cell variations in gene expression rates, which are then compared to experimental data.
References
Bessonnard S., De Mot L., Gonze D., Barriol M., Dennis C., Goldbeter A., Dupont G. and Chazaud C. (2014) Gata6, Nanog and Erk signaling control cell fate in the inner cell mass through a tristable regulatory network. Development 141, 3637-3648.
De Mot L., Gonze D., Bessonnard S., Chazaud C., Goldbeter A. and Dupont G. (2016) Cell fate specification based on tristability in the inner cell mass of mouse blastocysts. Biophys. J. 110, 710-722.
Tosenberger A., Gonze D., Bessonnard S., Cohen-Tannoudji M., Chazaud C. and Dupont G. (2017) A multiscale model of early cell lineage specification including cell division. NPJ Systems Biology and Applications, 3: 16.
Robert C., Prista von Bonhorst F., De Decker Y., Dupont G. and Gonze D. (2022) Initial source of heterogeneity in a model for cell fate decision in the early mammalian embryo. Interface Focus 12: 20220010.
