title: GATA-3 regulates the self-renewal of long-term hematopoietic stem cells.
abstract: The transcription factor GATA-3 is expressed and required for differentiation and function throughout the T lymphocyte lineage. Despite evidence it may also be expressed in multipotent hematopoietic stem cells (HSCs), any role for GATA-3 in these cells has remained unclear. Here we found GATA-3 was in the cytoplasm in quiescent long-term stem cells from steady-state bone marrow but relocated to the nucleus when HSCs cycled. Relocation depended on signaling via the mitogen-activated protein kinase p38 and was associated with a diminished capacity for long-term reconstitution after transfer into irradiated mice. Deletion of Gata3 enhanced the repopulating capacity and augmented the self-renewal of long-term HSCs in cell-autonomous fashion without affecting the cell cycle. Our observations position GATA-3 as a regulator of the balance between self-renewal and differentiation in HSCs that acts downstream of the p38 signaling pathway.
authors: 1] Ontario Cancer Institute, University Health Network, Toronto, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors: Catherine
authors: C
authors: Frelin
authors: Robert
authors: R
authors: Herrington
authors: Salima
authors: S
authors: Janmohamed
authors: Mary
authors: M
authors: Barbara
authors: Gary
authors: G
authors: Tran
authors: Christopher J
authors: CJ
authors: Paige
authors: Patricia
authors: P
authors: Benveniste
authors: Juan-Carlos
authors: JC
authors: Zuñiga-Pflücker
authors: Abdallah
authors: A
authors: Souabni
authors: Meinrad
authors: M
authors: Busslinger
authors: Norman N
authors: NN
authors: Iscove
mesh_terms: D000818:Animals; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D015870:Gene Expression; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D011070:Poly I-C / Q000494:pharmacology; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D050990:GATA3 Transcription Factor; D008024:Ligands; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D011070:Poly I-C
references: Mol Syst Biol. 2011 Aug 30;7:526
references: 21878914
references: Cell Stem Cell. 2007 Aug 16;1(2):218-29
references: 18371352
references: Nat Immunol. 2003 Jul;4(7):708-13
references: 12766767
references: PLoS Genet. 2008 Dec;4(12):e1000316
references: 19112489
references: J Pharmacol Exp Ther. 2001 Feb;296(2):312-21
references: 11160612
references: Curr Biol. 1995 Aug 1;5(8):909-22
references: 7583149
references: Genes Dev. 2011 Nov 1;25(21):2227-41
references: 22056668
references: Blood. 2002 Aug 15;100(4):1287-93
references: 12149209
references: J Immunol. 2007 Dec 1;179(11):7808-19
references: 18025227
references: J Immunol. 2007 Feb 15;178(4):2491-8
references: 17277157
references: Blood. 1991 Sep 1;78(5):1237-40
references: 1878591
references: Blood. 2011 Aug 4;118(5):1291-3
references: 21670475
references: Development. 2006 Jan;133(1):53-61
references: 16319112
references: Bioorg Med Chem Lett. 2001 May 7;11(9):1123-6
references: 11354358
references: Blood. 2001 Apr 15;97(8):2257-68
references: 11290586
references: J Immunol. 2012 Oct 1;189(7):3271-83
references: 22997230
references: J Biol Chem. 2007 Feb 23;282(8):5101-5
references: 17170104
references: Nat Med. 2009 Jun;15(6):696-700
references: 19483695
references: Cell Immunol. 2007 Jun;247(2):72-84
references: 17927969
references: Nat Biotechnol. 2009 Jan;27(1):84-90
references: 19060879
references: Cell. 2008 Dec 12;135(6):1118-29
references: 19062086
references: Stem Cells Dev. 2011 Jul;20(7):1143-52
references: 21198398
references: Nature. 2009 Apr 16;458(7240):904-8
references: 19212321
references: Bioorg Med Chem Lett. 2001 Nov 5;11(21):2867-70
references: 11597418
references: Cell. 2005 Jul 1;121(7):1109-21
references: 15989959
references: Cancer Res. 2005 Oct 1;65(19):9029-37
references: 16204077
references: Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2448-53
references: 15695585
references: Curr Biol. 1997 Oct 1;7(10):805-8
references: 9368765
references: Blood. 2012 Mar 8;119(10):2242-51
references: 22267605
references: Blood. 2009 Jun 18;113(25):6342-50
references: 19377048
references: Blood. 1997 May 15;89(10):3596-606
references: 9160664
references: Blood. 2004 Dec 15;104(13):4157-64
references: 15315972
references: Genome Res. 2011 Apr;21(4):555-65
references: 21233399
references: Cell. 2006 Dec 1;127(5):1041-55
references: 17129787
references: J Exp Med. 1995 Jan 1;181(1):93-103
references: 7807027
references: Nat Rev Immunol. 2009 Feb;9(2):125-35
references: 19151747
references: Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20286-90
references: 19095794
references: Cell Stem Cell. 2010 Jan 8;6(1):48-58
references: 20074534
references: Nat Med. 2006 Apr;12(4):446-51
references: 16565722
references: J Immunol. 2007 Feb 15;178(4):2008-17
references: 17277104
references: J Exp Med. 2009 Dec 21;206(13):2987-3000
references: 19934022
references: J Immunol. 2012 Mar 15;188(6):2825-33
references: 22323545
references: Cancer Res. 2007 Jul 1;67(13):6477-83
references: 17616709
references: Nat Rev Immunol. 2010 Mar;10(3):201-9
references: 20182459
references: Nat Biotechnol. 2002 Sep;20(9):940-3
references: 12172558
references: Bioorg Med Chem Lett. 1998 Nov 17;8(22):3111-6
references: 9873686
references: Blood. 1996 Oct 15;88(8):2852-8
references: 8874181
references: Blood. 1993 Mar 15;81(6):1497-504
references: 8453096