Ras-MAPK signaling promotes trophectoderm formation from embryonic stem cells and mouse embryos

Lu, Chi-Wei; Yabuuchi, Akiko; Chen, Lingyi; Viswanathan, Srinivas R.; Kim, Kitai; Daley, George Q.

doi:10.1038/ng.173

Cited by 142 publications

(128 citation statements)

References 29 publications

(3 reference statements)

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“…In addition to the ExEn lineage, we also detected elevated expression of some trophectoderm marker genes after overexpression of Stk40, which is in agreement with a recent finding that inducible induction of Ras at low levels promoted expression of marker genes for both trophectoderm and primitive endoderm lineages (29). However, they also found that trophectoderm markers predominated at higher levels of Ras (29).…”

Section: Discussionsupporting

confidence: 80%

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Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation

Sun

Gao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Self-renewal and differentiation of embryonic stem cells (ESCs) are controlled by intracellular transcriptional factors and extracellular factor-activated signaling pathways. Transcription factor Oct4 is a key player maintaining ESCs in an undifferentiated state, whereas the Erk/MAPK pathway is known to be important for ESC differentiation. However, the manner in which intracellular pluripotency factors modulate extracellular factor-activated signaling pathways in ESCs is not well understood. Here, we report identification of a target gene of Oct4, serine/threonine kinase 40 (Stk40), which is able to activate the Erk/MAPK pathway and induce extraembryonicendoderm (ExEn) differentiation in mouse ESCs. Interestingly, cells overexpressing Stk40 exclusively contribute to the ExEn layer of chimeric embryos when injected into host blastocysts. In contrast, deletion of Stk40 in ESCs markedly reduces ExEn differentiation in vitro. Mechanistically, Stk40 interacts with Rcn2, which also activates Erk1/2 to induce ExEn specification in mouse ESCs. Moreover, Rcn2 proteins are specifically located in the cytoplasm of the ExEn layer of early mouse embryos. Importantly, knockdown of Rcn2 blocks Stk40-activated Erk1/2 and ESC differentiation. Therefore, our study establishes a link between the pluripotency factor Oct4 and the Erk/MAPK signaling pathway, and it uncovers cooperating signals in the Erk/ MAPK activation that control ExEn differentiation.embryonic stem cells | Rcn2 | Ras | Gata6

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Section: Discussionsupporting

confidence: 80%

“…However, they also found that trophectoderm markers predominated at higher levels of Ras (29). Thus, it seems that the effect of Ras activation is dependent on developmental and cellular contexts as well as its activation levels.…”

Section: Discussionmentioning

confidence: 98%

Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation

Sun

Gao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Subsequently, we generated a doxycycline-dependent knockdown stable ES cell line and the ES cells were injected into the nude mice as described [39] (Figure 6A). Teratoma development was monitored by determination of endoderm, mesoderm and ectoderm (Supplementary information, Figure S11C).…”

Section: The Effect Of Fbw7 On the Development Of Blood Vessels In A mentioning

confidence: 99%

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

Wang

Liu

et al. 2013

Cell Res

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F-box and WD repeat domain-containing 7 (FBW7), the substrate-binding subunit of E3 ubiquitin ligase SCF FBW7 (a complex of SKP1, cullin-1 and FBW7), plays important roles in various physiological and pathological processes. Although FBW7 is required for vascular development, its function in the endothelium remains to be investigated. In this study, we show that FBW7 is an important regulator of endothelial functions, including angiogenesis, leukocyte adhesion and the endothelial barrier integrity. Using RNA interference, we found that the depletion of FBW7 markedly impairs angiogenesis in vitro and in vivo. We identified the zinc finger transcription factor Krüppel-like factor 2 (KLF2) as a physiological target of FBW7 in endothelial cells. Knockdown of FBW7 expression resulted in the accumulation of endogenous KLF2 protein in endothelial cells. FBW7-mediated KLF2 destruction was shown to depend on the phosphorylation of KLF2 via glycogen synthase kinase-3 (GSK3) at two conserved phosphodegrons. Mutating these phosphodegron motifs abolished the FBW7-mediated degradation and ubiquitination of KLF2. The siRNAmediated knockdown of FBW7 showed that KLF2 is an essential target of FBW7 in the regulation of endothelial functions. Moreover, FBW7-mediated KLF2 degradation was shown to be critical for angiogenesis in teratomas and in zebrafish development. Taken together, our study suggests a role for FBW7 in the processes of endothelial cell migration, angiogenesis, inflammation and barrier integrity, and provides novel insights into the regulation of KLF2 stability in vivo.

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“…Knowledge of signaling pathways and transcription factors that reinforce these three lineages in the blastocyst has pointed to ways to alter the developmental potential of the stem cell lines derived from the blastocyst's lineages. For example, ESCs can be converted to TSCs by overexpressing the TE-specific transcription factor CDX2 in TSC medium [16] and by other means [17][18][19][20][21]. Importantly, overexpression of Cdx2 in ESCs leads to TSC-like cells with highly similar morphology, developmental potential, and gene expression as embryoderived TSCs [16,22,23].…”

Section: Introductionmentioning

confidence: 99%

Cdx2Efficiently Induces Trophoblast Stem-Like Cells in Naïve, but Not Primed, Pluripotent Stem Cells

Blij

Parenti

Tabatabai-Yazdi

et al. 2015

Stem Cells and Development

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Ras-MAPK signaling promotes trophectoderm formation from embryonic stem cells and mouse embryos

Cited by 142 publications

References 29 publications

Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation

Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

Cdx2Efficiently Induces Trophoblast Stem-Like Cells in Naïve, but Not Primed, Pluripotent Stem Cells

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