Nanog is the gateway to the pluripotent ground state.
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.
Silva
Jose
J
Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Cambridge CB2 1QR, UK. jcs64@cscr.cam.ac.uk
Nichols
Jennifer
J
Theunissen
Thorold W
TW
Guo
Ge
G
van Oosten
Anouk L
AL
Barrandon
Ornella
O
Wray
Jason
J
Yamanaka
Shinya
S
Chambers
Ian
I
Smith
Austin
A
D053687:Adult Stem Cells / Q000166:cytology; D000818:Animals; D001755:Blastocyst / Q000166:cytology; D054337:Cell Dedifferentiation; D065150:Cellular Reprogramming; D053595:Embryonic Stem Cells / Q000166:cytology; D005260:Female; D005855:Germ Layers / Q000166:cytology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000071317:Nanog Homeobox Protein; D014960:X Chromosome / Q000378:metabolism
D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse
Nature. 2007 Jul 12;448(7150):196-9
17597760
Curr Biol. 2001 Oct 2;11(19):1553-8
11591326
Development. 2009 Oct;136(19):3215-22
19710168
Cell. 2003 May 30;113(5):631-42
12787504
Cell. 2008 Jun 13;133(6):1106-17
18555785
Science. 2004 Jan 30;303(5658):644-9
14671313
Nature. 2006 Jun 22;441(7096):997-1001
16791199
Development. 2007 Oct;134(19):3549-63
17827181
Nature. 2007 Jul 19;448(7151):313-7
17554338
Nature. 2007 Jul 12;448(7150):191-5
17597762
Science. 2004 Jan 30;303(5658):666-9
14752160
Nat Med. 2009 Jul;15(7):814-8
19491843
Int Rev Exp Pathol. 1983;24:63-133
6302028
Genes Dev. 2008 Mar 15;22(6):746-55
18347094
Cell. 2008 Feb 22;132(4):567-82
18295576
Cell. 2009 Jan 23;136(2):364-77
19167336
Cell. 1976 Sep;9(1):45-55
61820
EMBO J. 1997 Nov 3;16(21):6510-20
9351832
Dev Biol. 1994 Nov;166(1):259-67
7958450
FEBS Lett. 2009 Jun 5;583(11):1721-7
19327353
Cell. 2006 Aug 25;126(4):663-76
16904174
Cell. 1983 Oct;34(3):1053-62
6627391
Development. 2001 Jun;128(12):2333-9
11493552
Cell. 2008 Mar 21;132(6):1049-61
18358816
Cell Stem Cell. 2009 Jun 5;4(6):487-92
19497275
Cell. 2005 Sep 23;122(6):947-56
16153702
J Embryol Exp Morphol. 1985 Dec;90:379-88
3834036
Cell Stem Cell. 2007 Jun 7;1(1):55-70
18371336
Nature. 2007 Jul 19;448(7151):318-24
17554336
Nature. 1981 Jul 9;292(5819):154-6
7242681
Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9290-5
18579772
Gene Expr Patterns. 2005 Jun;5(5):639-46
15939376
Nature. 2008 May 22;453(7194):519-23
18497825
Proc Natl Acad Sci U S A. 1997 May 27;94(11):5709-12
9159137
Oncogene. 2004 Sep 20;23(43):7150-60
15378075
Cell. 2008 Feb 22;132(4):532-6
18295569
Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10294-10299
16801560
Dev Cell. 2006 May;10(5):615-24
16678776
Cell. 1998 Oct 30;95(3):379-91
9814708
Nat Genet. 2006 Apr;38(4):431-40
16518401
Nature. 2008 Jul 31;454(7204):646-50
18594515
PLoS Biol. 2008 Oct 21;6(10):e253
18942890
Nature. 2006 Nov 16;444(7117):364-8
17093407
Proc Natl Acad Sci U S A. 1981 Dec;78(12):7634-8
6950406
PLoS Biol. 2005 Sep;3(9):e283
16086633
Bioessays. 2006 Feb;28(2):128-45
16435291
Development. 2009 Apr;136(7):1063-9
19224983
Cell. 2007 Nov 30;131(5):861-72
18035408
Genes Dev. 2003 Jan 1;17(1):126-40
12514105
J Embryol Exp Morphol. 1984 Apr;80:225-40
6747527
Development. 2007 Dec;134(23):4219-31
17978007
Nature. 2007 Dec 20;450(7173):1230-4
18097409
Science. 2008 Sep 19;321(5896):1693-5
18802003
Development. 2008 Mar;135(5):909-18
18263842
J Cell Sci Suppl. 1988;10:11-27
3077932
Science. 2007 Dec 21;318(5858):1917-20
18029452
Dev Cell. 2003 Apr;4(4):481-95
12689588
Cell. 2003 May 30;113(5):643-55
12787505