FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment

Kunath, Tilo; Saba-El-Leil, Marc K.; Almousailleakh, Marwa; Wray, Jason; Meloche, Sylvain; Smith, Austin

doi:10.1242/dev.02880

Cited by 722 publications

(775 citation statements)

References 48 publications

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“…We conclude that not only are soluble GAGs capable of modulating neural specification in a HS-competent background but also that sulfation patterning/ charge is critically important in defining this effect. In almost all conditions, the Sox1 þ patterns are largely comparable at later stages (7þ days, data not shown) suggesting that GAGs are influencing growth factor signaling during loss of selfrenewal and transition to the ''primed state'' for differentiation [26,33]. To test this, we compared 46Cs differentiated with heparin present for 10 days with cultures where heparin was removed at day 4 ( Fig.…”

Section: Soluble Heparin-like Saccharides Can Influence Neural Specifmentioning

confidence: 98%

“…We then used the Ext1 À/À ES cell line to show that, although in the absence of cell surface HS ES cells fail to achieve successful neuroectodermal differentiation, this can be compensated by soluble heparin [25]. In this study, we have interrogated the specific role of HS in early signaling events during exit from self renewal into primitive ectoderm and subsequently neuroectoderm [26][27][28]. We have used the 46C ES cell line to investigate the effect of glycosaminoglycan (GAG) addition to HS-competent cells, demonstrating that GAG can be a positive or negative regulator of differentiation, dependent on size and sulfation pattern of the chains.…”

Section: Introductionmentioning

confidence: 99%

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Specific Glycosaminoglycans Modulate Neural Specification of Mouse Embryonic Stem Cells

et al. 2011

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Mouse embryonic stem (mES) cells express a low sulfated form of heparan sulfate (HS). HS chains displayed by ES cells and their progeny become more complex and more sulfated during progression from pluripotency to neuroectodermal precursors. Sulfated epitopes are important for recognition and binding of a variety of ligands including members of the fibroblast growth factor (FGF) family. We demonstrated previously that mES cells lacking HS cannot undergo neural specification but this activity can be recovered by adding soluble heparin, a highly sulfated glycosaminoglycan (GAG). Therefore, we hypothesized that soluble GAGs might be used to support neural differentiation of HS competent cells and that the mechanisms underlying this activity might provide useful information about the signaling pathways critical for loss of pluripotency and early lineage commitment. In this study, we demonstrate that specific HS/heparin polysaccharides support formation of Sox1 1 neural progenitor cells from wild-type ES cells. This effect is dependent on sulfation pattern, concentration, and length of saccharide. Using a selective inhibitor of FGF signal transduction, we show that heparin modulates signaling events regulating exit from pluripotency and commitment to primitive ectoderm and subsequently neuroectoderm. Interestingly, we were also able to demonstrate that multiple receptor tyrosine kinases were influenced by HS in this system. This suggests roles for additional factors, possibly in cell proliferation or protection from apoptosis, during the process of neural specification. Therefore, we conclude that soluble GAGs or synthetic mimics could be considered as suitable low-cost factors for addition to ES cell differentiation regimes. STEM CELLS 2011;29:629-640 Disclosure of potential conflicts of interest is found at the end of this article.

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Section: Soluble Heparin-like Saccharides Can Influence Neural Specifmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Specific Glycosaminoglycans Modulate Neural Specification of Mouse Embryonic Stem Cells

et al. 2011

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“…Supporting the idea that heterogeneity is a direct physiological consequence of the balance between self‐renewal and differentiation, TF expression becomes uniformly high as a result of pharmacological treatment with PD0325901 (Wray et al , 2010). This MEK inhibitor blocks ESC differentiation by preventing the pro‐differentiative action of autocrine FGF4 (Kunath et al , 2007; Stavridis et al , 2007), a direct target gene of OCT4 and SOX2 (Ambrosetti et al , 1997). Therefore, fractionating ESC populations cultured in LIF/FCS on the basis of heterogeneous TF expression has the potential to clarify mechanisms underlying the ability of ESCs to respond to autocrine signaling stimuli, dismantle the naïve pluripotency network, and exit self‐renewal.…”

Section: Introductionmentioning

confidence: 99%

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

et al. 2018

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Self‐renewal of embryonic stem cells (ESCs) cultured in LIF/fetal calf serum (FCS) is incomplete with some cells initiating differentiation. While this is reflected in heterogeneous expression of naive pluripotency transcription factors (TFs), the link between TF heterogeneity and differentiation is not fully understood. Here, we purify ESCs with distinct TF expression levels from LIF/FCS cultures to uncover early events during commitment from naïve pluripotency. ESCs carrying fluorescent Nanog and Esrrb reporters show Esrrb downregulation only in Nanoglow cells. Independent Esrrb reporter lines demonstrate that Esrrbnegative ESCs cannot effectively self‐renew. Upon Esrrb loss, pre‐implantation pluripotency gene expression collapses. ChIP‐Seq identifies different regulatory element classes that bind both OCT4 and NANOG in Esrrbpositive cells. Class I elements lose NANOG and OCT4 binding in Esrrbnegative ESCs and associate with genes expressed preferentially in naïve ESCs. In contrast, Class II elements retain OCT4 but not NANOG binding in ESRRB‐negative cells and associate with more broadly expressed genes. Therefore, mechanistic differences in TF function act cumulatively to restrict potency during exit from naïve pluripotency.

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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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FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment

Abstract: . Fibroblast growth factor (FGF) signaling through PI 3-kinase and Akt/PKB is required for embryoid body differentiation.

Cited by 722 publications

References 48 publications

Specific Glycosaminoglycans Modulate Neural Specification of Mouse Embryonic Stem Cells

Specific Glycosaminoglycans Modulate Neural Specification of Mouse Embryonic Stem Cells

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

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

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