ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification.
Although many genes are known to be critical for early hematopoiesis in the embryo, it remains unclear whether distinct regulatory pathways exist to control hematopoietic specification versus hematopoietic stem cell (HSC) emergence and function. Due to their interaction with key regulators of hematopoietic commitment, particular interest has focused on the role of the ETS family of transcription factors; of these, ERG is predicted to play an important role in the initiation of hematopoiesis, yet we do not know if or when ERG is required. Using in vitro and in vivo models of hematopoiesis and HSC development, we provide strong evidence that ERG is at the center of a distinct regulatory program that is not required for hematopoietic specification or differentiation but is critical for HSC maintenance during embryonic development. We show that, from the fetal period, ERG acts as a direct upstream regulator of Gata2 and Runx1 gene activity. Without ERG, physiological HSC maintenance fails, leading to the rapid exhaustion of definitive hematopoiesis.
Molecular Medicine Division, The Walter and Eliza Institute of Medical Research, Melbourne, Parkville, Victoria 3052, Australia. taoudi@wehi.edu.au
Samir
S
Taoudi
Thomas
T
Bee
Adrienne
A
Hilton
Kathy
K
Knezevic
Julie
J
Scott
Tracy A
TA
Willson
Caitlin
C
Collin
Tim
T
Thomas
Anne K
AK
Voss
Benjamin T
BT
Kile
Warren S
WS
Alexander
John E
JE
Pimanda
Douglas J
DJ
Hilton
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG
D050676:Core Binding Factor Alpha 2 Subunit; C531115:ERG protein, mouse; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D015513:Oncogene Proteins; C493726:Runx1 protein, mouse; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG
Nature. 1995 Feb 2;373(6513):432-4
7830794
Circ Res. 2009 May 8;104(9):1049-57
19359602
Development. 2005 Mar;132(5):1117-26
15689374
Dev Cell. 2005 Mar;8(3):365-75
15737932
EMBO J. 2000 Jun 1;19(11):2465-74
10835345
Nature. 2003 Jan 30;421(6922):547-51
12540851
Int J Dev Biol. 2005;49(2-3):279-84
15906242
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):840-5
17213321
Blood. 2000 Apr 1;95(7):2284-8
10733497
Immunity. 2003 May;18(5):699-711
12753746
Blood. 2009 Jul 9;114(2):268-78
19420357
Blood. 2008 Mar 15;111(6):3005-14
18184866
Blood. 2005 Mar 15;105(6):2340-2
15550486
Cell Stem Cell. 2010 Oct 8;7(4):532-44
20887958
Immunity. 2002 May;16(5):661-72
12049718
Cell. 2005 Jul 1;121(7):1109-21
15989959
PLoS Biol. 2004 Mar;2(3):E75
15024423
Blood. 2006 Jul 15;108(2):737-44
16569764
Nature. 2009 Feb 12;457(7231):887-91
19129762
Nat Immunol. 2008 Jul;9(7):810-9
18500345
Cancer Res. 2005 Sep 1;65(17):7596-602
16140924
Blood. 2005 Jan 1;105(1):95-102
15367440
Blood. 2006 Jun 15;107(12):4737-45
16484587
BMC Dev Biol. 2009 Dec 23;9:72
20030844
Immunity. 2000 Oct;13(4):423-31
11070161
Curr Protoc Stem Cell Biol. 2008 Aug;Chapter 2:Unit 2A.8.1-2A.8.14
18729047
Blood. 2007 Mar 1;109(5):1908-16
17053063
Proc Natl Acad Sci U S A. 2007 May 29;104(22):9399-403
17517650
Cell. 2007 Aug 10;130(3):470-83
17655922
Curr Protoc Stem Cell Biol. 2008 Jan;Chapter 2:Unit 2A.6
18770635
Mol Cell Biol. 2000 Aug;20(15):5643-52
10891501
Blood. 2008 Apr 15;111(8):4413-4; author reply 4414-5
18398056
Genes Dev. 2006 May 1;20(9):1175-86
16651658
Blood. 2007 Dec 15;110(13):4188-97
17823307
Cell Immunol. 2001 Dec 15;214(2):110-22
12088410
J Exp Med. 2004 Oct 4;200(7):871-82
15466621
Nature. 2010 Mar 4;464(7285):116-20
20154729
Blood. 2004 Nov 15;104(10):3097-105
15251982
EMBO J. 2008 Jul 9;27(13):1886-95
18528438
Development. 2005 Sep;132(18):4179-91
16107475
Nature. 1994 Sep 15;371(6494):221-6
8078582
Development. 2002 Nov;129(21):4891-9
12397098
Cell. 1996 Sep 20;86(6):897-906
8808625
Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):134-9
15623562
Circ Res. 2008 Nov 7;103(10):1147-54
18832752
Blood. 2005 May 15;105(10):3871-4
15677556
Blood. 2009 May 28;113(22):5456-65
19346495
Cell. 1996 Jul 12;86(1):47-57
8689686
Blood. 2008 Apr 1;111(7):3498-506
18195090
Nat Med. 2004 Mar;10(3):299-304
14966519
Gene Expr Patterns. 2007 Jun;7(6):657-65
17517537
Immunity. 2000 Aug;13(2):167-77
10981960
Cancer Cell. 2010 May 18;17(5):443-54
20478527
Cell. 1996 Jan 26;84(2):321-30
8565077
Cell Stem Cell. 2008 Jul 3;3(1):99-108
18593562
Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3444-9
8622955
Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17692-7
17962413