Lineage Establishment and Progression within the Inner Cell Mass of the Mouse Blastocyst Requires FGFR1 and FGFR2

Kang, Min‐Jung; Garg, Vidur; Hadjantonakis, Anna‐Katerina

doi:10.1016/j.devcel.2017.05.003

Cited by 141 publications

(272 citation statements)

References 61 publications

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“…One obvious possible explanation is that the TE cells lack Fgfr2 and are not responsive to Fgf4 to activate the Fgf/Ras/Erk1/2 pathway. However, Fgfr1 and Fgfr2 are expressed, and their signaling plays a compensatory role in TE proliferation (Kang et al, 2017; Molotkov et al, 2017). Alternatively, an Erk1/2 substrate(s) responsible for suppressing or promoting GATA6 expression in PrE progenitor cells is not expressed in the TE cells.…”

Section: Discussionmentioning

confidence: 99%

“…Lack of PrE formation in knockout embryos of Fgf4 (Rappolee et al, 1994; Feldman et al, 1995; Goldin and Papaioannou, 2003; Kang et al, 2013; Krawchuk et al, 2013), Fgfr2 (Yamanaka et al, 2010; Arman et al, 1998), or Grb2 (Cheng et al, 1998; Chazaud et al, 2006), components of the Ras/MAPK pathway, leads to the conclusion that the FGF/FGFR/Ras/MAPK signaling pathway is also required for the development of PrE (Chazaud and Yamanaka, 2016; Kuijk et al, 2012). Recent analyses also indicate that both Fgfr1 and Fgfr2 play roles in the embryonic cells for exit from the pluripotent state and commitment to PrE lineage, with dominant contribution from Fgfr1 in preimplantation development (Kang et al, 2017; Molotkov et al, 2017). Additional analyses indicate that Ras/MAPK signaling is upstream of GATA6, since ectopic expression of GATA6 is sufficient to bypass the requirement of Grb2 (Wang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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GATA6 phosphorylation by Erk1/2 propels exit from pluripotency and commitment to primitive endoderm

Meng

Moore

Tao

et al. 2018

Developmental Biology

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The transcription factor GATA6 and the Fgf/Ras/MAPK signaling pathway are essential for the development of the primitive endoderm (PrE), one of the two lineages derived from the pluripotent inner cell mass (ICM) of mammalian blastocysts. A mutant mouse line in which Gata6-coding exons are replaced with H2BGFP (histone H2B Green Fluorescence Protein fusion protein) was developed to monitor Gata6 promoter activity. In the Gata6-H2BGFP heterozygous blastocysts, the ICM cells that initially had uniform GFP fluorescence signal at E3.5 diverged into two populations by the 64-cell stage, either as the GFP-high PrE or the GFP-low epiblasts (Epi). However in the GATA6-null blastocysts, the originally moderate GFP expression subsided in all ICM cells, indicating that the GATA6 protein is required to maintain its own promoter activity during PrE linage commitment. In embryonic stem cells, expressed GATA6 was shown to bind and activate the Gata6 promoter in PrE differentiation. Mutations of a conserved serine residue (S264) for Erk1/2 phosphorylation in GATA6 protein drastically impacted its ability to activate its own promoter. We conclude that phosphorylation of GATA6 by Erk1/2 compels exit from pluripotent state, and the phosphorylation propels a GATA6 positive feedback regulatory circuit to compel PrE differentiation. Our findings resolve the longstanding question on the dual requirements of GATA6 and Ras/MAPK pathway for PrE commitment of the pluripotent ICM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GATA6 phosphorylation by Erk1/2 propels exit from pluripotency and commitment to primitive endoderm

Meng

Moore

Tao

et al. 2018

Developmental Biology

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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

Bessonnard

Bassalert

Coqueran

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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“…FGFR1 plays a major role in PrE cell specification as demonstrated by recent studies of the phenotype of Fgfr1 knockouts . Fgfr2 inactivation does not affect PrE formation but exacerbates the phenotype of Fgfr1 mutants . PDGF signaling also plays critical roles in PrE biology.…”

Section: Introductionmentioning

confidence: 97%

“…Several receptor tyrosine kinase (RTK) signaling pathways are thought to orchestrate Epi/PrE formation including FGF and PDGF signaling. FGF4/FGFR1/FGFR2 are critical for PrE specification [11][12][13][14]. Indeed, genetic and pharmacological modulation of FGF activity directly impacts on cell lineage decision so that gain of FGF activity favor PrE commitment whereas a loss of FGF activity favors Epi cell fate [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

PDGF Signaling in Primitive Endoderm Cell Survival Is Mediated by PI3K-mTOR Through p53-Independent Mechanism

et al. 2019

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Receptor tyrosine kinase signaling pathways are key regulators for the formation of the primitive endoderm (PrE) and the epiblast (Epi) from the inner cell mass (ICM) of the mouse preimplantation embryo. Among them, FGF signaling is critical for PrE cell specification, whereas PDGF signaling is critical for the survival of committed PrE cells. Here, we investigated possible functional redundancies among FGF, PDGF, and KIT signaling and showed that only PDGF signaling is involved in PrE cell survival. In addition, we analyzed the effectors downstream of PDGFRα. Our results suggest that the role of PDGF signaling in PrE cell survival is mediated through PI3K‐mTOR and independently from p53. Lastly, we uncovered a role for PI3K‐mTOR signaling in the survival of Epi cells. Taken together, we propose that survival of ICM cell lineages relies on the regulation of PI3K‐mTOR signaling through the regulation of multiple signaling pathways. Stem Cells 2019;37:888–898

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Lineage Establishment and Progression within the Inner Cell Mass of the Mouse Blastocyst Requires FGFR1 and FGFR2

Cited by 141 publications

References 61 publications

GATA6 phosphorylation by Erk1/2 propels exit from pluripotency and commitment to primitive endoderm

GATA6 phosphorylation by Erk1/2 propels exit from pluripotency and commitment to primitive endoderm

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

PDGF Signaling in Primitive Endoderm Cell Survival Is Mediated by PI3K-mTOR Through p53-Independent Mechanism

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