Nanog Is the Gateway to the Pluripotent Ground State
Open accessAbstract
Pluripotency is generated naturally during mammalian development through formation of the epiblast, founder tissue of the embryo proper. Pluripotency can be recreated by somatic cell reprogramming. Here we present evidence that the homeodomain protein Nanog mediates acquisition of both embryonic and induced pluripotency. Production of pluripotent hybrids by cell fusion is promoted by and dependent on Nanog. In transcription factor-induced molecular reprogramming, Nanog is initially dispensable but becomes essential for dedifferentiated intermediates to transit to ground state pluripotency. In the embryo, Nanog specifically demarcates the nascent epiblast, coincident with the domain of X chromosome reprogramming. Without Nanog, pluripotency does not develop, and the inner cell mass is trapped in a pre-pluripotent, indeterminate state that is ultimately nonviable. These findings suggest that Nanog choreographs synthesis of the naive epiblast ground state in the embryo and that this function is recapitulated in the culmination of somatic cell reprogramming.
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ICM cell fate specification is driven in part by lineage-specific TFs Gata6 and Nanog, co-expressed in uncommitted ICM and exclusively expressed in and required for PrE and EPI respectively.
“ICM cell fate specification is driven in part by the lineage-specific transcription factors (TFs) Gata6 and Nanog, which are co-expressed in uncommitted ICM, and exclusively expressed in, and required for, PrE and EPI respectively23,24.”
From The emergent landscape of the mouse gut endoderm at single-cell resolution (2019) · cites this paper as [23]
The Results section on Nanog localization (page not provided) identifies Gata6 as a hypoblast specification factor and reports that Gata6 and Nanog occupy mutually exclusive cells by E4.5. The Discussion (page not provided) says Nanog is exclusively expressed in nascent epiblast and is essential for its transition to pluripotency. Our copy does not establish that Gata6 and Nanog are co-expressed in uncommitted ICM cells or that Gata6 is required for primitive endoderm formation. (LLM, conf=0.88)
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Takahashi, K., & Yamanaka, S. (2006) · Cell · doi:10.1016/j.cell.2006.07.024 · Cited by 26,673 · see citing works
Self-citationThe ground state of embryonic stem cell self-renewal
Ying, Q.-L., Wray, J., Nichols, J., Batlle-Morera, L., Doble, B., Woodgett, J., Cohen, P., & Smith, A. (2008) · Nature · doi:10.1038/nature06968 · Cited by 3,442 · see citing works
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Research works printed but not linked: 56
- Avilion A.A. Nicolis S.K. Pevny L.H. Perez L. Vivian N. Lovell-Badge R. Multipotent cell lineages in early mouse development depend on SOX2 function Genes Dev. 17 2003 126 140 12514105 PMC195970
- Boyer L.A. Lee T.I. Cole M.F. Johnstone S.E. Levine S.S. Zucker J.P. Guenther M.G. Kumar R.M. Murray H.L. Jenner R.G. Core transcriptional regulatory circuitry in human embryonic stem cells Cell 122 2005 947 956 16153702 PMC3006442
- Brons I.G. Smithers L.E. Trotter M.W. Rugg-Gunn P. Sun B. Chuva de Sousa Lopes S.M. Howlett S.K. Clarkson A. Ahrlund-Richter L. Pedersen R.A. Derivation of pluripotent epiblast stem cells from mammalian embryos Nature 448 2007 191 195 17597762
- Brook F.A. Gardner R.L. The origin and efficient derivation of embryonic stem cells in the mouse Proc. Natl. Acad. Sci. USA 94 1997 5709 5712 9159137 PMC20843
- Chambers I. Smith A. Self-renewal of teratocarcinoma and embryonic stem cells Oncogene 23 2004 7150 7160 15378075
- Chambers I. Colby D. Robertson M. Nichols J. Lee S. Tweedie S. Smith A. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells Cell 113 2003 643 655 12787505
- Chambers I. Silva J. Colby D. Nichols J. Nijmeijer B. Robertson M. Vrana J. Jones K. Grotewold L. Smith A. Nanog safeguards pluripotency and mediates germline development Nature 450 2007 1230 1234 18097409
- Chazaud C. Yamanaka Y. Pawson T. Rossant J. Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway Dev. Cell 10 2006 615 624 16678776
- Chen X. Xu H. Yuan P. Fang F. Huss M. Vega V.B. Wong E. Orlov Y.L. Zhang W. Jiang J. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells Cell 133 2008 1106 1117 18555785
- Cole M.F. Johnstone S.E. Newman J.J. Kagey M.H. Young R.A. Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells Genes Dev. 22 2008 746 755 18347094 PMC2275428
- Conti L. Pollard S.M. Gorba T. Reitano E. Toselli M. Biella G. Sun Y. Sanzone S. Ying Q.L. Cattaneo E. Niche-independent symmetrical self-renewal of a mammalian tissue stem cell PLoS Biol. 3 2005 1596 1606 PMC1184591 16086633
- Dietrich J.E. Hiiragi T. Stochastic patterning in the mouse pre-implantation embryo Development 134 2007 4219 4231 17978007
- Evans M.J. Kaufman M.H. Establishment in culture of pluripotential cells from mouse embryos Nature 292 1981 154 156 7242681
- Gardner R.L. Origin and differentiation of extra-embryonic tissues in the mouse Int. Rev. Exp. Pathol. 24 1983 63 133 6302028
- Gardner R.L. Beddington R.S. Multi-lineage ‘stem’ cells in the mammalian embryo J. Cell Sci. Suppl. 10 1988 11 27 3077932
- Guo G. Yang J. Nichols J. Hall J.S. Eyres I. Mansfield W. Smith A. Klf4 reverts developmentally programmed restriction of ground state pluripotency Development 136 2009 1063 1069 19224983 PMC2685927
- Jaenisch R. Young R. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming Cell 132 2008 567 582 18295576 PMC4142810
- Kim J. Chu J. Shen X. Wang J. Orkin S.H. An extended transcriptional network for pluripotency of embryonic stem cells Cell 132 2008 1049 1061 18358816 PMC3837340
- Kim J.B. Zaehres H. Wu G. Gentile L. Ko K. Sebastiano V. Arauzo-Bravo M.J. Ruau D. Han D.W. Zenke M. Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors Nature 454 2008 646 650 18594515
- Lavial F. Acloque H. Bertocchini F. Macleod D.J. Boast S. Bachelard E. Montillet G. Thenot S. Sang H.M. Stern C.D. The Oct4 homologue PouV and Nanog regulate pluripotency in chicken embryonic stem cells Development 134 2007 3549 3563 17827181
- Loh Y.H. Wu Q. Chew J.L. Vega V.B. Zhang W. Chen X. Bourque G. George J. Leong B. Liu J. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells Nat. Genet. 38 2006 431 440 16518401
- Maherali N. Sridharan R. Xie W. Utikal J. Eminli S. Arnold K. Stadtfeld M. Yachechko R. Tchieu J. Jaenisch R. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution Cell Stem Cell 1 2007 55 70 18371336
- Mak W. Nesterova T.B. de Napoles M. Appanah R. Yamanaka S. Otte A.P. Brockdorff N. Reactivation of the paternal X chromosome in early mouse embryos Science 303 2004 666 669 14752160
- Martin G.R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells Proc. Natl. Acad. Sci. USA 78 1981 7634 7638 6950406 PMC349323
- Miller R.A. Ruddle F.H. Pluripotent teratocarcinoma-thymus somatic cell hybrids Cell 9 1976 45 55 61820
- Mitsui K. Tokuzawa Y. Itoh H. Segawa K. Murakami M. Takahashi K. Marauyama M. Maeda M. Yamanaka S. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells Cell 113 2003 631 642 12787504
- Navarro P. Avner P. When X-inactivation meets pluripotency: an intimate rendezvous FEBS Lett. 583 2009 1721 1727 19327353
- Navarro P. Chambers I. Karwacki-Neisius V. Chureau C. Morey C. Rougeulle C. Avner P. Molecular coupling of Xist regulation and pluripotency Science 321 2008 1693 1695 18802003
- Nichols J. Gardner R.L. Heterogeneous differentiation of external cells in individual isolated early mouse inner cell masses in culture J. Embryol. Exp. Morphol. 80 1984 225 240 6747527
- Nichols J. Smith A. Naive and Primed Pluripotent States Cell Stem Cell 4 2009 487 492 19497275
- Nichols J. Zevnik B. Anastassiadis K. Niwa H. Klewe-Nebenius D. Chambers I. Scholer H. Smith A. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4 Cell 95 1998 379 391 9814708
- Nichols J. Chambers I. Taga T. Smith A.G. Physiological rationale for responsiveness of mouse epiblast and embryonic stem cells to gp130 cytokines Development 128 2001 2333 2339 11493552
- Nichols J. Silva J. Roode M. Smith A. Suppression of Erk signalling promotes pluripotency in the mouse embryo Development 2009 PMC2739140 19710168
- Nichols J. Jones K. Phillips J.M. Newland S.A. Roode M. Mansfield W. Smith A. Cooke A. Validated germline-competent embryonic stem cell lines from nonobese diabetic mice Nat. Med. 15 2009 814 818 19491843
- Okamoto I. Otte A.P. Allis C.D. Reinberg D. Heard E. Epigenetic dynamics of imprinted X inactivation during early mouse development Science 303 2004 644 649 14671313
- Okita K. Ichisaka T. Yamanaka S. Generation of germline-competent induced pluripotent stem cells Nature 448 2007 313 317 17554338
- Palmieri S.L. Peter W. Hess H. Scholer H.R. Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation Dev. Biol. 166 1994 259 267 7958450
- Rastan S. Robertson E.J. X-chromosome deletions in embryo-derived (EK) cell lines associated with lack of X-chromosome inactivation J. Embryol. Exp. Morphol. 90 1985 379 388 3834036
- Selwood L. Johnson M.H. Trophoblast and hypoblast in the monotreme, marsupial and eutherian mammal: evolution and origins Bioessays 28 2006 128 145 16435291
- Silva J. Smith A. Capturing pluripotency Cell 132 2008 532 536 18295569 PMC2427053
- Silva J. Mak W. Zvetkova I. Appanah R. Nesterova T.B. Webster Z. Peters A.H. Jenuwein T. Otte A.P. Brockdorff N. Establishment of histone h3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 polycomb group complexes Dev. Cell 4 2003 481 495 12689588
- Silva J. Chambers I. Pollard S. Smith A. Nanog promotes transfer of pluripotency after cell fusion Nature 441 2006 997 1001 16791199
- Silva J. Barrandon O. Nichols J. Kawaguchi J. Theunissen T.W. Smith A. Promotion of reprogramming to ground state pluripotency by signal inhibition PLoS Biol. 6 2008 e253 18942890 PMC2570424
- Sridharan R. Tchieu J. Mason M.J. Yachechko R. Kuoy E. Horvath S. Zhou Q. Plath K. Role of the murine reprogramming factors in the induction of pluripotency Cell 136 2009 364 377 19167336 PMC3273494
- Suzuki A. Raya A. Kawakami Y. Morita M. Matsui T. Nakashima K. Gage F.H. Rodriguez-Esteban C. Izpisua Belmonte J.C. Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells Proc. Natl. Acad. Sci. USA 103 2006 10294 10299 16801560 PMC1502451
- Tada M. Tada T. Lefebvre L. Barton S.C. Surani M.A. Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells EMBO J. 16 1997 6510 6520 9351832 PMC1170256
- Tada M. Takahama Y. Abe K. Nakatsuji N. Tada T. Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells Curr. Biol. 11 2001 1553 1558 11591326
- Takagi N. Yoshida M.A. Sugawara O. Sasaki M. Reversal of X-inactivation in female mouse somatic cells hybridized with murine teratocarcinoma stem cells in vitro Cell 34 1983 1053 1062 6627391
- Takahashi K. Tanabe K. Ohnuki M. Narita M. Ichisaka T. Tomoda K. Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors Cell 131 2007 861 872 18035408
- Tesar P.J. Chenoweth J.G. Brook F.A. Davies T.J. Evans E.P. Mack D.L. Gardner R.L. McKay R.D. New cell lines from mouse epiblast share defining features with human embryonic stem cells Nature 448 2007 196 199 17597760
- Toyooka Y. Shimosato D. Murakami K. Takahashi K. Niwa H. Identification and characterization of subpopulations in undifferentiated ES cell culture Development 135 2008 909 918 18263842
- Wang J. Rao S. Chu J. Shen X. Levasseur D.N. Theunissen T.W. Orkin S.H. A protein interaction network for pluripotency of embryonic stem cells Nature 444 2006 364 368 17093407
- Wang W. Lin C. Lu D. Ning Z. Cox T. Melvin D. Wang X. Bradley A. Liu P. Chromosomal transposition of PiggyBac in mouse embryonic stem cells Proc. Natl. Acad. Sci. USA 105 2008 9290 9295 18579772 PMC2440425
- Wernig M. Meissner A. Foreman R. Brambrink T. Ku M. Hochedlinger K. Bernstein B.E. Jaenisch R. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state Nature 448 2007 318 324 17554336
- Yamaguchi S. Kimura H. Tada M. Nakatsuji N. Tada T. Nanog expression in mouse germ cell development Gene Expr. Patterns 5 2005 639 646 15939376
- Yu J. Vodyanik M.A. Smuga-Otto K. Antosiewicz-Bourget J. Frane J.L. Tian S. Nie J. Jonsdottir G.A. Ruotti V. Stewart R. Induced pluripotent stem cell lines derived from human somatic cells Science 318 2007 1917 1920 18029452
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- Authors
- Silva, J., Nichols, J., Theunissen, T. W., Guo, G., van Oosten, A. L., Barrandon, O., Wray, J., Yamanaka, S., Chambers, I., & Smith, A.
- Affiliations
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Kyoto University (JP)
- MRC Centre for Regenerative Medicine (GB)
- Corresponding author
- Smith, Austin
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 138
- Issue
- 4
- Pages
- 722-737
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3437554
- OpenAlex
- W2151870437
- Cited by
- 1,031
- References
- 2
- Citations by year
- 2026: 20 · 2025: 19 · 2024: 33 · 2023: 39 · 2022: 32 · 2021: 67 · 2020: 52 · 2019: 52 · 2018: 53 · 2017: 56 · 2016: 75 · 2015: 63 · 2014: 78 · 2013: 95 · 2012: 95
- FWCI
- 39.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Wellcome Trust
- Directorate for Biological Sciences
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- Nanog, pluripotency, naive pluripotency, epiblast, somatic cell reprogramming, induced pluripotent stem cells, cell fusion, inner cell mass, homeodomain transcription factor, mammalian embryo development
- MeSH terms
- Nanog Homeobox Protein, Animals, Blastocyst, Female, Germ Layers, X Chromosome, Homeodomain Proteins, Mice, Embryonic Stem Cells, Adult Stem Cells, Cell Dedifferentiation, Cellular Reprogramming
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