The transcription factor TCFAP2C/AP-2gamma cooperates with CDX2 to maintain trophectoderm formation.
In mammals, cell lineage specification is established at the blastocyst stage. At this stage, transcription factor Cdx2 represses pluripotency genes, thus promoting extraembryonic trophoblast fate. Recently, transcription factor Gata3 was shown to act in a parallel pathway in promoting trophoblast cell fate, suggesting that there are more factors working in the trophoblast lineage. Here, we report that the transcription factor Tcfap2c is expressed at a high level in the trophectoderm and is able to induce trophoblast fate in embryonic stem cells. Trophoblast fate induced by Tcfap2c does not require Cdx2 and vice versa, suggesting that the molecules act in alternative pathways. However, both Tcfap2c and Cdx2 are required for the upregulation of Elf5, a marker of trophoblast stem cell maintenance, suggesting that both factors are required for stable trophoblast induction. Tcfap2c-induced trophoblast-like cells are stable in long-term culture, indicating that they are capable of self-renewal. Tcfap2c-controlled trophoblast maintenance involves the induction of Cdx2 and the repression of the pluripotency factor Nanog. Tcfap2c-induced trophoblast-like cells differentiate to trophoblast derivatives in vitro and contribute to the trophectoderm in blastocysts in vivo. Taken together, these observations suggest that Tcfap2c and Cdx2 cooperate to override the pluripotency program and establish the extraembryonic trophoblast maintenance program in murine embryos.
Kuckenberg
Peter
P
Department of Developmental Pathology, Institute of Pathology, University of Bonn Medical School, Sigmund-Freud-Str. 25, Bonn D-53127, Germany.
Buhl
Sandra
S
Woynecki
Tatiana
T
van Fürden
Betina
B
Tolkunova
Elena
E
Seiffe
Friederike
F
Moser
Markus
M
Tomilin
Alexey
A
Winterhager
Elke
E
Schorle
Hubert
H
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D002478:Cells, Cultured; D047108:Embryonic Development / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000071317:Nanog Homeobox Protein; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology / Q000502:physiology
D015415:Biomarkers; D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; C583890:Tfap2c protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors
Biol Reprod. 2006 Sep;75(3):324-33
16672719
Development. 2007 Nov;134(21):3827-36
17913785
Dev Cell. 2009 Mar;16(3):398-410
19289085
Nature. 1981 Jul 9;292(5819):154-6
7242681
Cell Res. 2009 Sep;19(9):1052-61
19564890
Dev Biol. 2004 Jul 1;271(1):26-37
15196947
Dev Biol. 2004 Nov 1;275(1):158-69
15464579
Development. 2005 Aug;132(15):3393-403
15987772
Mech Dev. 2008 Mar-Apr;125(3-4):270-83
18083014
Life Sci. 2001 Sep 21;69(18):2157-65
11669459
Mol Cell Biol. 2002 May;22(9):3149-56
11940672
Cell Cycle. 2009 May 15;8(10):1515-25
19377304
Genesis. 2006 Jan;44(1):23-8
16400644
Mol Cell Biol. 2009 May;29(10):2748-61
19289495
Cell. 2005 Sep 23;122(6):947-56
16153702
Nature. 2000 Mar 2;404(6773):95-9
10716450
Cell. 2005 Dec 2;123(5):917-29
16325584
J Biol Chem. 2009 Oct 16;284(42):28729-37
19700764
Gene Expr Patterns. 2006 Aug;6(6):589-95
16414310
Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8424-8
8378314
Mol Reprod Dev. 1995 Jun;41(2):232-8
7654376
Science. 1998 Dec 11;282(5396):2072-5
9851926
Mol Cell Endocrinol. 2000 Feb 25;160(1-2):183-92
10715552
Mol Cancer Res. 2003 Oct;1(12):921-9
14573793
Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1292-6
7877970
Development. 2005 May;132(10):2299-308
15829518
Dev Cell. 2006 Mar;10(3):317-27
16516835
Genome Biol. 2005;6(13):246
16420676
Endocrinology. 2006 Sep;147(9):4319-29
16794002
Development. 2002 Jun;129(11):2733-47
12015300
Placenta. 2004 Apr;25 Suppl A:S32-8
15033304
Proc Natl Acad Sci U S A. 1981 Dec;78(12):7634-8
6950406
Nature. 1997 Mar 6;386(6620):84-7
9052785
Dev Biol. 1987 Feb;119(2):520-31
3803716
Development. 2010 Feb;137(3):395-403
20081188
Nat Genet. 2008 Jul;40(7):921-6
18536715
Stem Cells. 2006 Jan;24(1):139-44
16210407
Stem Cells. 2008 Apr;26(4):842-9
18192238
Nat Cell Biol. 2008 Nov;10(11):1280-90
18836439
Genome Res. 2010 Apr;20(4):458-72
20176728
Development. 2005 May;132(9):2093-102
15788452
Int J Dev Biol. 2000 Apr;44(3):253-65
10853822