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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: 42.35). 01/2008; 450(7173):1230-4. DOI: 10.1038/nature06403
Source: PubMed

ABSTRACT 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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    • "As no second (attracting) stable state exists, cells rapidly return to their origin and, thus, exhibit pulsing Nanog dynamics (Fig. 3A, bottom). This model predicted that excursions from the NH state are transient, providing a very short window of opportunity in which perturbations can become consolidated into a lineage commitment decision (Chambers et al., 2007). "
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    ABSTRACT: The maintenance of pluripotency in embryonic stem cells (ESCs), its loss during lineage specification or its re-induction to generate induced pluripotent stem cells are central topics in stem cell biology. To uncover the molecular basis and the design principles of pluripotency control, a multitude of experimental, but also an increasing number of computational, studies have been published. Here, we consider recent reports that apply computational or mathematical modelling approaches to describe the regulatory processes that underlie cell fate decisions in mouse ESCs. We summarise the principles, the strengths and potentials but also the limitations of different computational strategies. © 2015. Published by The Company of Biologists Ltd.
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    • "(Fig EV2, Table EV1). As expected, the transcription factors Rex1 and Nanog appeared variably expressed in the ESC-FCS population (Chambers et al, 2007; Toyooka et al, 2008), but not in the ESC-2i population, for which a more homogeneous signaling state is expected (Wray et al, 2010). In ESC-FCS, the extent of expression variability for several other development-related genes was even higher; examples included the body-axis specifying signaling molecule Lefty1 and the DNA methyltransferase regulator Dnmt3l. "
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    • "Single-cell quantitative image analyses of immunostained Nanog:H2B-GFP Tg/+ ESCs maintained under different conditions further validated reporter efficacy (Figures 1B, S1E, and S1F). Moreover, we observed an increased correlation of reporter activity with NANOG protein for the Nanog:H2B- GFP transgene, compared to the targeted Nanog transcriptional reporter in the heterozygous TNGA ESCs (Chambers et al., 2007) (Figures S1E and S1F). These data suggest that the BAC transgenic reporters we constructed faithfully marked the pluripotent state in ESC cultures and could be used to probe Nanog expression dynamics at single-cell resolution. "
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