Regulation of the ERK signalling pathway in the developing mouse blastocyst

Azami, Takuya; Bassalert, Cecilia; Allègre, Nicolas; Estrella, Lorena Valverde; Pouchin, Pierre; Ema, Masatsugu; Chazaud, Claire

doi:10.1242/dev.177139

Cited by 30 publications

(42 citation statements)

References 66 publications

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“…Increased pERK, another marker of formative pluripotency, is required for activating downstream formative pluripotent gene regulatory networks (Kalkan et al, 2019;Azami et al, 2019). We find increased pERK in control E14 cells at 24 and 48h -LIF2i compared with total ERK, which does not change during differentiation, as determined by immunoblotting cell lysates (Fig.…”

Section: Inhibiting Arp2/3 Complex Activity Has No Effect On Exit From Naïve Self-renewal But Delays Entry Into Formative Pluripotencymentioning

confidence: 60%

Arp2/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification

Aloisio

Barber

2021

Preprint

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SummaryMouse embryonic stem cells (mESCs), a model for differentiation into primed epiblast-like cells (EpiLCs), have revealed transcriptional and epigenetic control of early embryonic development. The control and significance of morphological changes, however, remain less defined. We show marked changes in morphology and actin architectures during differentiation that depend on Arp2/3 complex but not formin activity. Inhibiting Arp2/3 complex activity pharmacologically or genetically does not block exit from naive pluripotency but attenuates increases in EpiLC markers. We find that inhibiting Arp2/3 complex activity delays formative pluripotency and causes globally defective lineage specification as indicated by RNA-sequencing, with significant effects on TBX3-depedendent transcriptional programs. We also identify two previously unreported indicators of mESC differentiation; MRTF and FHL2, which have inverse Arp2/3 complex-dependent nuclear translocation. Our findings on Arp2/3 complex activity in differentiation and the established role of formins in EMT indicate that these two actin nucleators regulate distinct modes of epithelial plasticity.HighlightsArp2/3 complex activity is necessary for morphology changes during differentiationArp2/3 complex activity regulates transcriptional markers of differentiationInhibiting Arp2/3 complex activity delays entry into formative pluripotencyArp2/3 complex activity-dependent shuttling of FHL2 and MRTF occurs in mESCs

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Section: Inhibiting Arp2/3 Complex Activity Has No Effect On Exit From Naïve Self-renewal But Delays Entry Into Formative Pluripotencymentioning

confidence: 60%

Arp2/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification

Aloisio

Barber

2021

Preprint

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“…The FGF4-mediated gene regulation involves several steps between the external receptor and the final gene expression 14,15 , and the gene regulatory network in Figure 1A simplified this pathway into one step. We used Hill functions to describe the simplified gene regulation.…”

Section: Resultsmentioning

confidence: 99%

ICM cells can be partitioned robustly through transient synchronization using secreted FGF4

Xu¹,

Trusina²,

Sneppen³

2020

Preprint

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The differentiation of ICM cells into epiblast (EPI) and primitive endoderm (PE) is central in embryonic development. It is known that FGF4 signaling is important in this process, but it remains unclear how cells can be correctly partitioned. Here we model the NANOG-GATA6-FGF4 network, and test all 64 logical regulatory combinations for their ability to partition a group of cells. We found that nearly all the logic combinations allowed for correct partitioning, including a minimal network where self-activation of NANOG and GATA6 was inactivated. However such self-activation increased the robustness of the system. Furthermore, the model also captured the reported changes in cell proportions in response to FGF perturbations. This constrains the possible regulatory logic and predicts the presence of an “OR” gate in cell-cell communication. We repeatedly found that FGF4 coordinated the decision in two phases: A convergence and a bifurcation phase. First FGF4 negative feedback drives the cells to a balanced “battle” state where most cells have intermediate levels of both regulators, thus being double positive. Subsequent bifurcation happens at constant FGF4 level. Together our results suggest that the frequently observed state of multipotency during differentiation may be an emergent phenomenon resulting from inter-cellular negative feedbacks.

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“…R. Soc. B 375: 20190562 the existence of two receptors for FGF4 (FGFR1 and FGFR2) and multiple feedback regulatory interactions taking place between receptor activation and transcription of their target genes [12,125,[154][155][156][157], if the pathway is distilled to its net output, as proposed (figure 3d(iv)), it results in a lateral inhibition mechanism, in which cells producing FGF4 generate a local high concentration of ligand that induces PrE fate among their neighbours (and consequently inhibits epiblast fate). In this scenario, FGF4 is assumed to be bound to the extracellular matrix, rather than to diffuse throughout the ICM [179,180].…”

Section: An Autonomous Scalable Way To Robustly Generate Cell-type Diversitymentioning

confidence: 99%

“…[94,128,[132][133][134][135]159,160]. Activation of the RTK-MAPK pathway by FGF4 is required to maintain GATA6 expression in ICM cells, and without it the PrE fails to form [136,146,152,153,157]. However, while PrE specification requires the presence of FGF4 produced by epiblast cells, the maturation of the epiblast lineage also requires FGF4 and the presence of PrE cells [125].…”

Section: Pre or Epiblast Identity Precedes Positionmentioning

confidence: 99%

Coordination between patterning and morphogenesis ensures robustness during mouse development

Saiz

Hadjantonakis

2020

Phil. Trans. R. Soc. B

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The mammalian preimplantation embryo is a highly tractable, self-organizing developmental system in which three cell types are consistently specified without the need for maternal factors or external signals. Studies in the mouse over the past decades have greatly improved our understanding of the cues that trigger symmetry breaking in the embryo, the transcription factors that control lineage specification and commitment, and the mechanical forces that drive morphogenesis and inform cell fate decisions. These studies have also uncovered how these multiple inputs are integrated to allocate the right number of cells to each lineage despite inherent biological noise, and as a response to perturbations. In this review, we summarize our current understanding of how these processes are coordinated to ensure a robust and precise developmental outcome during early mouse development. This article is part of a discussion meeting issue ‘Contemporary morphogenesis'.

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Regulation of the ERK signalling pathway in the developing mouse blastocyst

Cited by 30 publications

References 66 publications

Arp2/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification

Arp2/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification

ICM cells can be partitioned robustly through transient synchronization using secreted FGF4

Coordination between patterning and morphogenesis ensures robustness during mouse development

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