Gene expression profiling of differentiating embryonic stem cells expressing dominant negative fibroblast growth factor receptor 2

Meszaros, Renata; Åkerlund, Mikael; Hjalt, Tord; Durbeej, Madeleine; Ekblom, Peter

doi:10.1016/j.matbio.2006.10.013

Cited by 6 publications

(5 citation statements)

References 57 publications

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“…Our results also showed that FGFR2 is the key signaling receptor for exogenous FGF‐2 in hESCs, even though its expression is much lower than another FGF‐2‐cognate receptor, FGFR1. This is consistent with the role of FGFR2 during mammalian development, where FGFR2 regulates the outgrowth and maintenance of the ICM, basement membrane formation, and epithelial differentiation [41–44]. Simultaneously, this raises the issue of what the role of dominantly expressed FGFR1 is in hESCs.…”

Section: Discussionsupporting

confidence: 76%

A Complex Role for FGF-2 in Self-Renewal, Survival, and Adhesion of Human Embryonic Stem Cells

et al. 2009

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The transcription program that is responsible for the pluripotency of human ESCs (hESCs) is believed to be comaintained by exogenous fibroblast growth factor-2 (FGF-2), which activates FGF receptors (FGFRs) and stimulates the mitogen-activated protein kinase (MAPK) pathway. However, the same pathway is stimulated by insulin receptors, insulin-like growth factor 1 receptors, and epidermal growth factor receptors. This mechanism is further complicated by intracrine FGF signals. Thus, the molecular mechanisms by which FGF-2 promotes the undifferentiated growth of hESCs are unclear. Here we show that, in undifferentiated hESCs, exogenous FGF-2 stimulated the expression of stem cell genes while suppressing cell death and apoptosis genes. Inhibition of autocrine FGF signaling caused upregulation of differentiation-related genes and downregulation of stem cell genes. Thus, exogenous FGF-2 reinforced the pluripotency maintenance program of intracrine FGF-2 signaling. Consistent with this hypothesis, expression of endogenous FGF-2 decreased during hESC differentiation and FGF-2 knockdown-induced hESC differentiation. In addition, FGF-2 signaling via FGFR2 activated MAPK kinase/extracellular signal-regulated kinase and AKT kinases, protected hESC from stress-induced cell death, and increased hESC adhesion and cloning efficiency. This stimulation of self-renewal, cell survival, and adhesion by exogenous and endogenous FGF-2 may synergize to maintain the undifferentiated growth of hESCs. Stem Cells 2009;27:1847–1857

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Section: Discussionsupporting

confidence: 76%

A Complex Role for FGF-2 in Self-Renewal, Survival, and Adhesion of Human Embryonic Stem Cells

et al. 2009

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“…From our microarray studies, we primarily expected that the expression of genes involved in the conversion of stem cells to a polarized epithelium would be altered. Examples of such genes are Nanog and Zfp42 (Rex-1), which have been shown to be expressed at a higher level in EBs with defective fibroblast growth factor receptor signalling but which are normally suppressed during early developmental events (Meszaros et al 2007). However, we have noted no differences in the expression of these genes.…”

Section: Discussionmentioning

confidence: 99%

Laminin α1 domains LG4-5 are essential for the complete differentiation of visceral endoderm

et al. 2009

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The heterotrimeric basement membrane protein laminin-111 is essential for early mouse embryogenesis. Its beta1 and gamma1 chains are crucial for endoderm differentiation and for the formation of basement membranes, whereas alpha1 chain null mice only lack the extraembryonic Reichert's membrane. Nevertheless, mice deficient in the cell-binding alpha1 globular domains 4-5 (LG4-5) have a more severe phenotype than animals devoid of the whole alpha1 chain, as these domains are required for the formation of a polarized ectoderm. However, the influence of the alpha1LG4-5 domains on endoderm differentiation is unclear. We have used microarray analysis to compare the expression profiles of normal and alpha1LG4-5-deficient embryoid bodies and show that genes encoding secreted plasma proteins and proteins involved in endocytosis are reduced in alpha1LG4-5-deficient embryoid bodies, indicating incomplete differentiation of the visceral endoderm. Moreover, mice lacking alpha1LG4-5 display endoderm disorganization and a defective expression of the endoderm marker Dab2. We hypothesize that alpha1LG4-5 domains provide an autocrine signal necessary for the complete differentiation of a functional visceral endoderm and vital signals for the polarization of the epiblast.

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“…In a recent study, we conducted an extensive microarray-based gene expression analysis of dnFgfr2-transfected EBs and presented a catalogue of genes whose expression was significantly influenced by deficient Fgfr signalling. Among the strongly downregulated targets, a number of not yet annotated genes were identified, including the hitherto uncharacterized gene 1110032E23Rik (Meszaros et al, 2007). As confirmed by RTInt.…”

Section: Abstract: Ened Embryonic Development Epithelium Fgf/fgfrmentioning

confidence: 80%

“…PCR analysis, the expression level of this gene was reduced in dnFgfr2 EBs, indicating that this novel gene might be a target of the Fgfr signalling pathway (Meszaros et al, 2007). In the current study, we investigated the gene expression of 1110032E23Rik during mouse and Xenopus laevis embryonic development.…”

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confidence: 92%

Expression of the novel gene Ened during mouse and Xenopus embryonic development

Meszaros¹,

Strate²,

Pera³

et al. 2008

Int. J. Dev. Biol.

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We have recently identified 1110032E23Rik as a down-regulated target gene in Fgf receptor-signalling-deficient mouse embryoid bodies. Here, we present the expression pattern of this novel gene, designated Ened (Expressed in Nerve and Epithelium during Development), in mouse and Xenopus laevis embryos. Murine Ened transcripts were first seen at E9.5 in the heart and the gastrointestinal tract. At later stages of gestation, expression could be found in the floor plate, peripheral nervous system, lens epithelium, skin, midline dorsal aorta, lung, kidney and testis. In Xenopus, the expression of the Ened orthologue displayed common RNA distribution in several ectodermal and mesodermal tissues, but also distinct expression in locations including the brain, notochord and blood islands. We suggest that Ened might be a novel target gene of the Fgfr signalling pathway during embryonic development, and that its expression could be modulated by the basement membrane component laminin-111. KEY WORDS: Ened, embryonic development, epithelium, Fgf/Fgfr signalling, peripheral nerveFibroblast growth factors (Fgfs) and their receptors (Fgfrs) have been shown to play important roles in the regulation of cellular proliferation and of subsequent differentiation and tissue patterning during vertebrate embryogenesis (Böttcher and Niehrs, 2005). Embryoid bodies (EBs) are aggregates of in vitro-cultured embryonic stem cells and an established model to study the role of Fgfs in epithelial morphogenesis (Weitzer, 2006). It has previously been demonstrated that EBs, in which endogenous Fgfr signalling was attenuated by the over-expression of dominant-negative Fgfr2 (dnFgfr2), failed to produce the first epithelial layer of the EBs, i.e. the endoderm. In addition, expression of the networkforming basement membrane proteins laminin-111 and collagen type IV was abrogated in Fgfr signalling-deficient EBs, and as a consequence ectoderm differentiation failed . In a recent study, we conducted an extensive microarray-based gene expression analysis of dnFgfr2-transfected EBs and presented a catalogue of genes whose expression was significantly influenced by deficient Fgfr signalling. Among the strongly downregulated targets, a number of not yet annotated genes were identified, including the hitherto uncharacterized gene 1110032E23Rik (Meszaros et al., 2007). As confirmed by RTInt.

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Gene expression profiling of differentiating embryonic stem cells expressing dominant negative fibroblast growth factor receptor 2

Cited by 6 publications

References 57 publications

A Complex Role for FGF-2 in Self-Renewal, Survival, and Adhesion of Human Embryonic Stem Cells

A Complex Role for FGF-2 in Self-Renewal, Survival, and Adhesion of Human Embryonic Stem Cells

Laminin α1 domains LG4-5 are essential for the complete differentiation of visceral endoderm

Expression of the novel gene Ened during mouse and Xenopus embryonic development

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