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Nanog Is the Gateway to the Pluripotent Ground State
Jose Silva1,2,6,,,Jennifer Nichols1,3,6,Thorold W. Theunissen1,2,Ge Guo1,2,Anouk L. van Oosten1,2,Ornella Barrandon1,2,Jason Wray1,2,Shinya Yamanaka4,Ian Chambers5andAustin Smith1,2,,
1 Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
2 Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
3 Department of Physiology, Development, and Neuroscience, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
4 Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
5 MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, King's Buildings, Edinburgh EH9 3JQ, UK
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.
