title: Hes1 desynchronizes differentiation of pluripotent cells by modulating STAT3 activity.
abstract: Robust development of the early embryo may benefit from mechanisms that ensure that not all pluripotent cells differentiate at exactly the same time: such mechanisms would build flexibility into the process of lineage allocation. This idea is supported by the observation that pluripotent stem cells differentiate at different rates in vitro. We use a clonal commitment assay to confirm that pluripotent cells commit to differentiate asynchronously even under uniform differentiation conditions. Stochastic variability in expression of the Notch target gene Hes1 has previously been reported to influence neural versus mesodermal differentiation through modulation of Notch activity. Here we report that Hes1 also has an earlier role to delay exit from the pluripotent state into all lineages. The early function of Hes1 to delay differentiation can be explained by an ability of Hes1 to amplify STAT3 responsiveness in a cell-autonomous manner. Variability in Hes1 expression therefore helps to explain why STAT3 responsiveness varies between individual ES cells, and this in turn helps to explain why pluripotent cells commit to differentiate asynchronously.
authors: MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors: Xinzhi
authors: X
authors: Zhou
authors: Andrew J H
authors: AJ
authors: Smith
authors: Anna
authors: A
authors: Waterhouse
authors: Guillaume
authors: G
authors: Blin
authors: Mattias
authors: M
authors: Malaguti
authors: Chia-Yi
authors: CY
authors: Lin
authors: Rodrigo
authors: R
authors: Osorno
authors: Ian
authors: I
authors: Chambers
authors: Sally
authors: S
authors: Lowell
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D015536:Down-Regulation; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D000071317:Nanog Homeobox Protein; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014162:Transfection
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C475540:Nanog protein, mouse; C494087:Stat3 protein, mouse
keywords: Embryonic Stem Cells; Hes1; LIF; Notch; Stat3
references: Nat Cell Biol. 2004 Jun;6(6):547-54
references: 15156153
references: Development. 1997 Mar;124(6):1139-48
references: 9102301
references: Gene. 1991 Dec 15;108(2):193-9
references: 1660837
references: Nature. 2002 Apr 4;416(6880):545-8
references: 11932748
references: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11292-7
references: 17592117
references: Nature. 2007 Jul 12;448(7150):196-9
references: 17597760
references: Cell. 2006 Sep 8;126(5):995-1004
references: 16959577
references: Nature. 1988 Dec 15;336(6200):688-90
references: 3143917
references: Nature. 2007 Dec 20;450(7173):1230-4
references: 18097409
references: PLoS One. 2009 Jul 30;4(7):e6438
references: 19649273
references: Development. 2008 Mar;135(5):909-18
references: 18263842
references: Cereb Cortex. 2006 Jul;16 Suppl 1:i132-7
references: 16766699
references: Cell Stem Cell. 2009 Dec 4;5(6):597-609
references: 19951688
references: Cell. 2007 Jan 12;128(1):197-209
references: 17218265
references: Nature. 2007 Jul 12;448(7150):191-5
references: 17597762
references: Cell Stem Cell. 2010 May 7;6(5):468-78
references: 20452321
references: Blood. 1996 Oct 1;88(7):2488-94
references: 8839840
references: Mol Cell Biol. 1996 Jul;16(7):3490-503
references: 8668165
references: Nature. 2009 Jul 2;460(7251):118-22
references: 19571885
references: Int J Oncol. 2007 Aug;31(2):461-6
references: 17611704
references: PLoS Biol. 2006 May;4(5):e121
references: 16594731
references: Curr Opin Genet Dev. 2006 Aug;16(4):413-8
references: 16793257
references: Circ Res. 2006 Jun 23;98(12):1471-8
references: 16690879
references: Nature. 2008 May 22;453(7194):519-23
references: 18497825
references: Cell. 2003 Oct 31;115(3):281-92
references: 14636556
references: Development. 2011 Sep;138(17):3593-612
references: 21828089
references: Oncogene. 2004 Sep 20;23(43):7150-60
references: 15378075
references: Development. 1998 May;125(9):1747-57
references: 9521912
references: Genes Dev. 1995 Dec 15;9(24):3136-48
references: 8543157
references: Development. 2000 Sep;127(18):3913-21
references: 10952889
references: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3789-94
references: 9108056
references: Cell Stem Cell. 2010 Sep 3;7(3):319-28
references: 20804969
references: BMC Cell Biol. 2007 Sep 04;8:40
references: 17784958
references: Genes Dev. 2009 Aug 15;23(16):1870-5
references: 19684110
references: Stem Cells. 2010 Oct;28(10):1772-81
references: 20715182
references: Development. 2010 Jul;137(13):2095-105
references: 20504958
references: Mech Dev. 2006 Jul;123(7):570-9
references: 16822655
references: Stem Cells. 2006 Apr;24(4):889-95
references: 16357342
references: Nature. 2006 Aug 17;442(7104):823-6
references: 16799564
references: Development. 2007 Apr;134(7):1243-51
references: 17329370
references: Stem Cells. 2006 Nov;24(11):2538-48
references: 16825607
references: Biochem Soc Trans. 2005 Dec;33(Pt 6):1518-21
references: 16246159
references: Methods Enzymol. 2006;418:151-69
references: 17141035
references: Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1683-8
references: 8643690
references: Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7963-8
references: 10859354
references: PLoS Biol. 2010 May 25;8(5):e1000379
references: 20520791
references: Cell. 2003 May 30;113(5):643-55
references: 12787505
references: Bioessays. 2012 Feb;34(2):110-8
references: 22215536
references: Nature. 1995 Sep 28;377(6547):355-8
references: 7566092
references: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4018-23
references: 12655061