Wnt Pathway Regulation of Embryonic Stem Cell Self-Renewal

Merrill, Bradley J.

doi:10.1101/cshperspect.a007971

Cited by 84 publications

(79 citation statements)

References 95 publications

(194 reference statements)

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“…While many reports indicated that the Wnt/b-catenin pathway is required for the establishment and self-renewal of ES cells (for example, Sato et al 2004;ten Berge et al 2011), others have found that its activation results in differentiation toward mesoderm and endoderm lineages (Lindsley et al 2006;Bakre et al 2007;Davidson et al 2012). Although some of these seemingly opposing differences can be attributed to differences between human and mouse ES cells, relative differences in levels of Wnt signaling are well known to affect cell fate outcome and could be a contributing factor (for review, see Merrill 2012). In this regard, it was recently reported that within human ES cell (hESC) populations, some cells are more Wnt-sensitive than others, and, upon differentiation, the Wnt(high) hESCs predominantly form endodermal and cardiac cells, whereas the Wnt(low) hESCs generate primarily neuroectodermal cells (Blauwkamp et al 2012).…”

Section: How Receiving Stem Cells Perceive External Wnt Cuesmentioning

confidence: 99%

Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling

2014

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In mammals, Wnt/b-catenin signaling features prominently in stem cells and cancers, but how and for what purposes have been matters of much debate. In this review, we summarize our current knowledge of Wnt/b-catenin signaling and its downstream transcriptional regulators in normal and malignant stem cells. We centered this review largely on three types of stem cells-embryonic stem cells, hair follicle stem cells, and intestinal epithelial stem cells-in which the roles of Wnt/b-catenin have been extensively studied. Using these models, we unravel how many controversial issues surrounding Wnt signaling have been resolved by dissecting the diversity of its downstream circuitry and effectors, often leading to opposite outcomes of Wnt/b-catenin-mediated regulation and differences rooted in stage-and context-dependent effects.

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Section: How Receiving Stem Cells Perceive External Wnt Cuesmentioning

confidence: 99%

Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling

2014

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“…Wnt signaling regulation plays key roles in both stem cell renewal and the differentiation of progenitor cell types (Merrill, 2012;Habib et al, 2013). In the mammalian intestinal epithelium, for example, loss of Apc and activation of Wnt signaling results in the maintenance of stem cell properties in the progenitor cells, a failure to differentiate, and the production of intestinal polyps that progress to malignant tumors (Schwitalla et al, 2013).…”

Section: Brat Specifies Inp Identity By Downregulating Arm Activity Vmentioning

confidence: 99%

“…The activation of Wnt signaling plays crucial roles in both the regulation of stem cell self-renewal and the generation of differentiated cells (Merrill, 2012;Habib et al, 2013). In the absence of Wnt ligand, Wnt signaling is negatively regulated by the destruction complex, which includes the kinases GSK3β and CKI, the scaffolding protein Axin, and the tumor suppressor Adenomatous polyposis coli (Apc) (Aoki and Taketo, 2007;MacDonald et al, 2009;Niehrs, 2012).…”

Section: Introductionmentioning

confidence: 99%

Brain tumor specifies intermediate progenitor cell identity by attenuating β-catenin/Armadillo activity

et al. 2014

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During asymmetric stem cell division, both the daughter stem cell and the presumptive intermediate progenitor cell inherit cytoplasm from their parental stem cell. Thus, proper specification of intermediate progenitor cell identity requires an efficient mechanism to rapidly extinguish the activity of self-renewal factors, but the mechanisms remain unknown in most stem cell lineages. During asymmetric division of a type II neural stem cell (neuroblast) in the Drosophila larval brain, the Brain tumor (Brat) protein segregates unequally into the immature intermediate neural progenitor (INP), where it specifies INP identity by attenuating the function of the self-renewal factor Klumpfuss (Klu), but the mechanisms are not understood. Here, we report that Brat specifies INP identity through its N-terminal B-boxes via a novel mechanism that is independent of asymmetric protein segregation. Brat-mediated specification of INP identity is critically dependent on the function of the Wnt destruction complex, which attenuates the activity of β-catenin/Armadillo (Arm) in immature INPs. Aberrantly increasing Arm activity in immature INPs further exacerbates the defects in the specification of INP identity and enhances the supernumerary neuroblast mutant phenotype in brat mutant brains. By contrast, reducing Arm activity in immature INPs suppresses supernumerary neuroblast formation in brat mutant brains. Finally, reducing Arm activity also strongly suppresses supernumerary neuroblasts induced by overexpression of klu. Thus, the Brat-dependent mechanism extinguishes the function of the selfrenewal factor Klu in the presumptive intermediate progenitor cell by attenuating Arm activity, balancing stem cell maintenance and progenitor cell specification.

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“…Several studies have demonstrated that the WNT/β-catenin signaling pathway is a critical regulator of stem cell self-renewal, and the hypothesis that WNT primarily acts to maintain stem cells in an undifferentiated state has garnered significant support (reviewed in refs. [1][2][3][4]. This paradigm is especially apparent in various adult stem cell populations, such as in skin, intestine, and blood, where WNT/β-catenin signaling is essential for proper tissue homeostasis.…”

mentioning

confidence: 99%

The WNT receptor FZD7 is required for maintenance of the pluripotent state in human embryonic stem cells

Fernández

Huggins

Perna

et al. 2014

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

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WNT signaling is involved in maintaining stem cells in an undifferentiated state; however, it is often unclear which WNTs and WNT receptors are mediating these activities. Here we examined the role of the WNT receptor FZD7 in maintaining human embryonic stem cells (hESCs) in an undifferentiated and pluripotent state. FZD7 expression is significantly elevated in undifferentiated cells relative to differentiated cell populations, and interfering with its expression or function, either by short hairpin RNA-mediated knockdown or with a fragment antigen binding (Fab) molecule directed against FZD7, disrupts the pluripotent state of hESCs. The FZD7-specific Fab blocks signaling by Wnt3a protein by downregulating FZD7 protein levels, suggesting that FZD7 transduces Wnt signals to activate Wnt/β-catenin signaling. These results demonstrate that FZD7 encodes a regulator of the pluripotent state and that hESCs require endogenous WNT/β-catenin signaling through FZD7 to maintain an undifferentiated phenotype. human pluripotent stem cell | self-renewal | differentiation

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Wnt Pathway Regulation of Embryonic Stem Cell Self-Renewal

Cited by 84 publications

References 95 publications

Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling

Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling

Brain tumor specifies intermediate progenitor cell identity by attenuating β-catenin/Armadillo activity

The WNT receptor FZD7 is required for maintenance of the pluripotent state in human embryonic stem cells

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