Abstract
Precise control and maintenance of population size is fundamental for organismal development and homeostasis. The three cell types of the mammalian blastocyst are generated in precise proportions over a short time, suggesting a mechanism to ensure a reproducible outcome. We developed a minimal mathematical model demonstrating growth factor signaling is sufficient to guarantee this robustness and which anticipates an embryo's response to perturbations in lineage composition. Addition of lineage-restricted cells both in vivo and in silico, causes a shift of the fate of progenitors away from the supernumerary cell type, while eliminating cells using laser ablation biases the specification of progenitors toward the targeted cell type. Finally, FGF4 couples fate decisions to lineage composition through changes in local growth factor concentration, providing a basis for the regulative abilities of the early mammalian embryo whereby fate decisions are coordinated at the population level to robustly generate tissues in the right proportions.
Highlights
Across metazoa, coordination between cell fate specification and population size ensures robust developmental outcomes
We show that Fibroblast growth factor 4 (FGF4) is the growth factor providing the feedback necessary to couple lineage size with cell fate decisions
Cell fate decisions in the inner cell mass of the blastocyst are made at the population level
Summary
Coordination between cell fate specification and population size ensures robust developmental outcomes. The preimplantation mammalian embryo is a paradigm of selforganization, where patterning and morphogenesis occur without the need for maternal determinants or external cues It provides an in vivo platform to understand the processes that ensure precision and robustness during the development of multicellular organisms. These embryos can tolerate cell loss, exemplified by preimplantation genetic diagnose (Harper and SenGupta, 2012), and can incorporate foreign cells to generate chimeric animals (Bradley et al, 1984; Gardner, 1968; Mintz, 1964; Mintz and Illmensee, 1975; Tachibana et al, 2012; Tarkowski, 1959; 1961). Despite recent interest in understanding and exploiting the capacity of early mammalian embryos and cells for self-organization (Bedzhov and ZernickaGoetz, 2014; Deglincerti et al, 2016; Harrison et al, 2017; Morgani et al, 2018a; Rivron et al, 2018; Shahbazi et al, 2019; Sozen et al, 2018; Warmflash et al, 2014), little is known about the local control mechanisms that enable such robust autonomous development
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