Smad2 Is Essential for Maintenance of the Human and Mouse Primed Pluripotent Stem Cell State

Sakaki-Yumoto, Masayo; Liu, Jianming; Ramalho-Santos, Miguel; Yoshida, Nobuaki; Derynck, Rik

doi:10.1074/jbc.m112.446591

Cited by 82 publications

(73 citation statements)

References 72 publications

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“…However, there are several reports that contradict this notion. In human embryonic stem cells, TGFβ/activin signaling requires SMAD2 instead of SMAD3/4 for the maintenance of pluripotency (Avery et al, 2010;Sakaki-Yumoto et al, 2013). These results indicate that the function RT-qPCR analysis of the mRNA levels of the indicated genes after the suppression of p38 signaling with SB203580 (20 μM) in the Smad2-mutant testes.…”

Section: Functions Of Smad Proteins In Testesmentioning

confidence: 69%

SMAD2 and p38 signaling pathways act in concert to determine XY primordial germ cell fate in mice

et al. 2015

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The sex of primordial germ cells (PGCs) is determined in developing gonads on the basis of cues from somatic cells. In XY gonads, sexdetermining region Y (SRY) triggers fibroblast growth factor 9 (FGF9) expression in somatic cells. FGF signaling, together with downstream nodal/activin signaling, promotes male differentiation in XY germ cells by suppressing retinoic acid (RA)-dependent meiotic entry and inducing male-specific genes. However, the mechanism by which nodal/activin signaling regulates XY PGC fate is unknown. We uncovered the roles of SMAD2/3 and p38 MAPK, the putative downstream factors of nodal/activin signaling, in PGC sexual fate decision. We found that conditional deletion of Smad2, but not Smad3, from XY PGCs led to a loss of male-specific gene expression. Moreover, suppression of RA signaling did not rescue male-specific gene expression in Smad2-mutant testes, indicating that SMAD2 signaling promotes male differentiation in a RA-independent manner. By contrast, we found that p38 signaling has an important role in the suppression of RA signaling. The Smad2 deletion did not disrupt the p38 signaling pathway even though Nodal expression was significantly reduced, suggesting that p38 was not regulated by nodal signaling in XY PGCs. Additionally, the inhibition of p38 signaling in the Smad2-mutant testes severely impeded XY PGC differentiation and induced meiosis. In conclusion, we propose a model in which p38 and SMAD2 signaling coordinate to determine the sexual fate of XY PGCs.

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Section: Functions Of Smad Proteins In Testesmentioning

confidence: 69%

SMAD2 and p38 signaling pathways act in concert to determine XY primordial germ cell fate in mice

et al. 2015

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“…SMAD2 is a member of the transforming growth factor (TGF)-β and activin-signaling pathway (Heyer et al, 1999). It is essential for maintaining the human and mouse primed pluripotent stem cell state (Sakaki-Yumoto et al, 2013). This protein is also a direct mediator of TGF-β signaling (Brown et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Identification of differently expressed genes in leukemia using multiple microarray datasets

Zhang¹,

Xu²,

Guo³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. The purpose of this study was to identify differentially expressed genes and analyze biological processes related to leukemia. A meta-analysis was performed using the Rank Product package of Gene Expression Omnibus datasets for leukemia. Next, Gene Ontology-enrichment analysis and pathway analysis were performed using the Gene Ontology website and Kyoto Encyclopedia of Genes and Genomes. A protein-protein interaction network was constructed using the Cytoscape software. Using the Rank Product package for leukemia, we identified a total of 1294 differentially expressed genes, 357 of which were not involved in individual differentially expressed genes. Gene Ontology-enrichment analyses showed that these 357 genes were enriched in biological processes such as mRNA metabolism, RNA splicing, and mRNA processing. Pathwayenrichment analysis showed that the genes were involved in the intestinal immune network for IgA production, endocytosis, and the mitogen-activated protein kinase signaling pathway. The proteinprotein interaction network indicated that HRAS, CD44, STAT1, SMAD2, and COPS5 were important in many interactions. Our study revealed genes that were consistently differentially expressed Differentially expressed genes in leukemia in leukemia, as well as the biological pathways and protein-protein interaction network associated with these genes.

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“…BMP and WNT could be required only to initiate and to stabilise this network, respectively. Accordingly, BMP plays a crucial role in vitro to block the protective activity of Activin/ Nodal signalling on pluripotency and to promote the induction of endoderm specification (Sakaki-Yumoto et al, 2013). Furthermore, WNT/β-catenin interacts with Smad2/3 target genes such as SOX17 to activate the expression of other genes such as FOXA2 (Sinner et al, 2004), which are essential for endoderm pattering and organogenesis.…”

Section: Activin/nodal Signalling As Inducer Of Endoderm Differentiationmentioning

confidence: 99%

Activin/Nodal signalling in stem cells

2015

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Activin/Nodal growth factors control a broad range of biological processes, including early cell fate decisions, organogenesis and adult tissue homeostasis. Here, we provide an overview of the mechanisms by which the Activin/Nodal signalling pathway governs stem cell function in these different stages of development. We describe recent findings that associate Activin/Nodal signalling to pathological conditions, focusing on cancer stem cells in tumorigenesis and its potential as a target for therapies. Moreover, we will discuss future directions and questions that currently remain unanswered on the role of Activin/Nodal signalling in stem cell selfrenewal, differentiation and proliferation.

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Smad2 Is Essential for Maintenance of the Human and Mouse Primed Pluripotent Stem Cell State

Cited by 82 publications

References 72 publications

SMAD2 and p38 signaling pathways act in concert to determine XY primordial germ cell fate in mice

SMAD2 and p38 signaling pathways act in concert to determine XY primordial germ cell fate in mice

Identification of differently expressed genes in leukemia using multiple microarray datasets

Activin/Nodal signalling in stem cells

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