Distinct Requirements for FGFR1 and FGFR2 in Primitive Endoderm Development and Exit from Pluripotency

Molotkov, Andrei; Mazot, Pierre; Brewer, J. Richard; Cinalli, Ryan M.; Soriano, Philippe

doi:10.1016/j.devcel.2017.05.004

Cited by 159 publications

(293 citation statements)

References 70 publications

(162 reference statements)

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“…Conversely, LIF acts by boosting expression of members of the network 22, 23, 24. Genetic perturbations have established that ERK1/2 signalling downstream of fibroblast growth factor 4 (FGF) is important for timely and efficient exit from the naïve state and subsequent commitment 15, 25, 26, 27, 28, 29, 30, 31. Consistent with this, inhibition of either FGF receptor or the MEK/ERK1/2 pathway markedly impedes ES cell differentiation 6, 32, 33.…”

Section: Introductionmentioning

confidence: 99%

Negative feedback via RSK modulates Erk‐dependent progression from naïve pluripotency

et al. 2018

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Mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated kinase (ERK) signalling is implicated in initiation of embryonic stem (ES) cell differentiation. The pathway is subject to complex feedback regulation. Here, we examined the ERK‐responsive phosphoproteome in ES cells and identified the negative regulator RSK1 as a prominent target. We used CRISPR/Cas9 to create combinatorial mutations in RSK family genes. Genotypes that included homozygous null mutations in Rps6ka1, encoding RSK1, resulted in elevated ERK phosphorylation. These RSK‐depleted ES cells exhibit altered kinetics of transition into differentiation, with accelerated downregulation of naïve pluripotency factors, precocious expression of transitional epiblast markers and early onset of lineage specification. We further show that chemical inhibition of RSK increases ERK phosphorylation and expedites ES cell transition without compromising multilineage potential. These findings demonstrate that the ERK activation profile influences the dynamics of pluripotency progression and highlight the role of signalling feedback in temporal control of cell state transitions.

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Section: Introductionmentioning

confidence: 99%

Negative feedback via RSK modulates Erk‐dependent progression from naïve pluripotency

et al. 2018

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“…Fibroblast Growth Factor (FGF)/Extracellular signal-Regulated Kinase (ERK) signaling pathway is considered as the main regulator of Epi/PrE lineage decision. Genetic inactivation of several members of the FGF pathway including Grb2 3 , Fgfr1/2 8,9 and Fgf4 10,11 impairs PrE formation. Similarly, pharmacological perturbation of FGF/ ERK activity also strongly affects PrE/Epi specification 12,13 .…”

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confidence: 99%

ICM conversion to epiblast by FGF/ERK inhibition is limited in time and requires transcription and protein degradation

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et al. 2017

Mechanisms of Development

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1Inner cell Mass (ICM) specification into epiblast (Epi) and primitive endoderm (PrE) is an asynchronous and progressive process taking place between E3.0 to E3.75 under the control of the Fibroblast Growth Factor (FGF)/Extracellular signal-Regulated Kinase (ERK) signaling pathway. Here, we have analyzed in details the kinetics of specification and found that ICM cell responsiveness to the up and down regulation of FGF signaling activity are temporally distinct. We also showed that PrE progenitors are generated later than Epi progenitors. We further demonstrated that, during this late phase of specification, a 4 hours period of FGF/ERK inhibition prior E3.75 is sufficient to convert ICM cells into Epi. Finally, we showed that ICM conversion into Epi in response to inhibition during this short time window requires both transcription and proteasome degradation. Collectively, our data give new insights into the timing and mechanisms involved in the process of ICM specification.During early mammalian development, two distinct differentiation steps occur during the formation of the blastocyst. The first one will generate the trophectoderm and the inner cell mass (ICM) followed by the specification of ICM cells into the epiblast (Epi) and the primitive endoderm (PrE). These events are highly coordinated and regulated by a limited number of transcription factors and cell signaling. Epi/PrE formation can be viewed as a three-step model 1 . First, blastomeres initially co-express the Epi marker NANOG and the PrE marker GATA6 until E3.25 (32-cells) 2 . Specification of both Epi and PrE is thought to occur asynchronously between E3.25 to E3.75 (64-cells) which is reflected by an ICM composition of cells expressing either NANOG or GATA6 3 . These two cell populations ultimately reorganize by a cell sorting process and, by E4.5 (>100 cells), the PrE forms a single cell layer in contact to the blastocoel cavity 2,4 . NANOG and GATA6 transcription factors are two key-lineage markers of Epi and PrE formation respectively and have been proposed to mutually repress each other. Indeed, all ICM cells adopt a PrE fate in Nanog mutant embryos 5 while a reverse situation is observed in Gata6 mutants 6,7 . Fibroblast Growth Factor (FGF)/Extracellular signal-Regulated Kinase (ERK) signaling pathway is considered as the main regulator of Epi/PrE lineage decision. Genetic inactivation of several members of the FGF pathway including Grb2 3 , Fgfr1/2 8,9 and Fgf4 10,11 impairs PrE formation. Similarly, pharmacological perturbation of FGF/ ERK activity also strongly affects PrE/Epi specification 12,13 . Indeed, when FGFR or MEK is inhibited, all ICM cells adopt an Epi fate. Reciprocally, ICM cells specify into PrE when embryos are cultured in presence of high dose of FGF4. ICM cell plasticity and responsiveness to modulations of FGF activity is progressively lost and around E4.0 cell lineages are determined [13][14][15] . In this study, we have examined in a greater temporal resolution the consequences of modulating FGF/ERK activity during...

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“…However, this mutant does not result in the complete removal of the FGFR2, but instead yields a truncated, albeit non-functional, receptor. On the other hand, removal of exon 5, common to both Fgfr2b and Fgfr2c isoforms, did not lead to the expression of a truncated receptor Molotkov et al, 2017]. In fact, there are slight phenotypic differences too between these knockouts, with the latter Fgfr2c knockout appearing less severe Molotkov et al, 2017].…”

Section: Discussionmentioning

confidence: 89%

“…On the other hand, removal of exon 5, common to both Fgfr2b and Fgfr2c isoforms, did not lead to the expression of a truncated receptor Molotkov et al, 2017]. In fact, there are slight phenotypic differences too between these knockouts, with the latter Fgfr2c knockout appearing less severe Molotkov et al, 2017]. Targeting constructs recombined between intragenic regions also have an effect on gene expression.…”

Section: Discussionmentioning

confidence: 96%

“…However, there are instances in the literature where a wide phenotypic spectrum can be produced. Examples of this can be seen in the Fgfr2 knockouts as the receptor protein has multiple functionalities Molotkov et al, 2017]. A common strategy to generate an Fgfr2 knockout is through the removal of the ligand-binding domain (exons 8-9, IgI loop3).…”

Section: Discussionmentioning

confidence: 99%

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Mouse Models of Syndromic Craniosynostosis

2018

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Craniosynostosis is a common craniofacial birth defect. This review focusses on the advances that have been achieved through studying the pathogenesis of craniosynostosis using mouse models. Classic methods of gene targeting which generate individual gene knockout models have successfully identified numerous genes required for normal development of the skull bones and sutures. However, the study of syndromic craniosynostosis has largely benefited from the production of knockin models that precisely mimic human mutations. These have allowed the detailed investigation of downstream events at the cellular and molecular level following otherwise unpredictable gain-of-function effects. This has greatly enhanced our understanding of the pathogenesis of this disease and has the potential to translate into improvement of the clinical management of this condition in the future.

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Distinct Requirements for FGFR1 and FGFR2 in Primitive Endoderm Development and Exit from Pluripotency

Cited by 159 publications

References 70 publications

Negative feedback via RSK modulates Erk‐dependent progression from naïve pluripotency

Negative feedback via RSK modulates Erk‐dependent progression from naïve pluripotency

ICM conversion to epiblast by FGF/ERK inhibition is limited in time and requires transcription and protein degradation

Mouse Models of Syndromic Craniosynostosis

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