Chambers, I. et al. Nanog safeguards pluripotency and mediates germline development. Nature 450, 1230-1234

MRC Centre Development in Stem Cell Biology, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JQ, UK.
Nature (Impact Factor: 41.46). 01/2008; 450(7173):1230-4. DOI: 10.1038/nature06403
Source: PubMed


Nanog is a divergent homeodomain protein found in mammalian pluripotent cells and developing germ cells. Deletion of Nanog causes early embryonic lethality, whereas constitutive expression enables autonomous self-renewal of embryonic stem cells. Nanog is accordingly considered a core element of the pluripotent transcriptional network. However, here we report that Nanog fluctuates in mouse embryonic stem cells. Transient downregulation of Nanog appears to predispose cells towards differentiation but does not mark commitment. By genetic deletion we show that, although they are prone to differentiate, embryonic stem cells can self-renew indefinitely in the permanent absence of Nanog. Expanded Nanog null cells colonize embryonic germ layers and exhibit multilineage differentiation both in fetal and adult chimaeras. Although they are also recruited to the germ line, primordial germ cells lacking Nanog fail to mature on reaching the genital ridge. This defect is rescued by repair of the mutant allele. Thus Nanog is dispensible for expression of somatic pluripotency but is specifically required for formation of germ cells. Nanog therefore acts primarily in construction of inner cell mass and germ cell states rather than in the housekeeping machinery of pluripotency. We surmise that Nanog stabilizes embryonic stem cells in culture by resisting or reversing alternative gene expression states.

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    • "). Surprisingly, TNGA (Nanog reporter; Chambers et al., 2007) and Rex1-GFP (Wray et al., 2011) mESCs maintained for multiple passages in serum plus LIF with iCRT3 exhibited enhanced expression of their respective pluripotency reporters (Fig. 2, A and B). In addition, cells maintained long term with iCRT3 showed enhanced expression of classic pluripotency genes compared with the DMSO control, whereas expression of differentiation markers and TCF target genes was concomitantly reduced (Fig. 2 C). "
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    ABSTRACT: The ability of mouse embryonic stem cells (mESCs) to self-renew or differentiate into various cell lineages is regulated by signaling pathways and a core pluripotency transcriptional network (PTN) comprising Nanog, Oct4, and Sox2. The Wnt/β-catenin pathway promotes pluripotency by alleviating T cell factor TCF3-mediated repression of the PTN. However, it has remained unclear how β-catenin’s function as a transcriptional activator with TCF1 influences mESC fate. Here, we show that TCF1-mediated transcription is up-regulated in differentiating mESCs and that chemical inhibition of β-catenin/TCF1 interaction improves long-term self-renewal and enhances functional pluripotency. Genetic loss of TCF1 inhibited differentiation by delaying exit from pluripotency and conferred a transcriptional profile strikingly reminiscent of self-renewing mESCs with high Nanog expression. Together, our data suggest that β-catenin’s function in regulating mESCs is highly context specific and that its interaction with TCF1 promotes differentiation, further highlighting the need for understanding how its individual protein–protein interactions drive stem cell fate.
    The Journal of Cell Biology 10/2015; 211(1):39-52. · 9.83 Impact Factor
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    • "Cell Stem Cell 17, 471–485, October 1, 2015 ª2015 The Authors 475 differentiation primed cells more pluripotency ground state cells cells on the differentiation path 169 cells 42 cells 39 cells Chambers et al., 2007 Singh et al., 2007 Toyooka et al., 2008 Kalmar et al., 2009 Canham et al., 2010 Faddah et al., 2013 Islam et al., 2013 "
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    ABSTRACT: Embryonic stem cell (ESC) culture conditions are important for maintaining long-term self-renewal, and they influence cellular pluripotency state. Here, we report single cell RNA-sequencing of mESCs cultured in three different conditions: serum, 2i, and the alternative ground state a2i. We find that the cellular transcriptomes of cells grown in these conditions are distinct, with 2i being the most similar to blastocyst cells and including a subpopulation resembling the two-cell embryo state. Overall levels of intercellular gene expression heterogeneity are comparable across the three conditions. However, this masks variable expression of pluripotency genes in serum cells and homogeneous expression in 2i and a2i cells. Additionally, genes related to the cell cycle are more variably expressed in the 2i and a2i conditions. Mining of our dataset for correlations in gene expression allowed us to identify additional components of the pluripotency network, including Ptma and Zfp640, illustrating its value as a resource for future discovery.
    Cell Stem Cell 10/2015; 17(4):471-485. DOI:10.1016/j.stem.2015.09.011 · 22.27 Impact Factor
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    • "In vitro, it has repeatedly been observed that mESCs are heterogeneous for expression of Nanog (Chambers et al., 2007). Although mPSCs can flux between Nanog + and Nanog – states in vitro, this is not reflected in the embryo in vivo, where, once epiblast cells become specified, they no longer move backwards in developmental time to give rise to primitive endoderm (Xenopoulos et al., 2015). "
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    ABSTRACT: In the mouse, naïve pluripotent stem cells (PSCs) are thought to represent the cell culture equivalent of the late epiblast in the pre-implantation embryo, with which they share a unique defining set of features. Recent studies have focused on the identification and propagation of a similar cell state in human. Although the capture of an exact human equivalent of the mouse naïve PSC remains an elusive goal, comparative studies spurred on by this quest are lighting the path to a deeper understanding of pluripotent state regulation in early mammalian development.
    Development 09/2015; 142(18):30910-3099. DOI:10.1242/dev.116061 · 6.46 Impact Factor
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