ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification
- Samir Taoudi1,2,6,
- Thomas Bee3,
- Adrienne Hilton1,
- Kathy Knezevic3,
- Julie Scott4,
- Tracy A. Willson1,2,
- Caitlin Collin1,
- Tim Thomas1,2,
- Anne K. Voss1,2,
- Benjamin T. Kile1,2,
- Warren S. Alexander2,5,
- John E. Pimanda3 and
- Douglas J. Hilton1,2
- 1Molecular Medicine Division, The Walter and Eliza Institute of Medical Research, Melbourne, Parkville, Victoria 3052, Australia;
- 2Department of Medical Biology, The University of Melbourne, Melbourne, Parkville, Victoria 3010, Australia;
- 3Lowy Cancer Research Centre, The Prince of Wales Clinical School, University of New South Wales, Sydney 2052, Australia;
- 4Microinjection Services, The Walter and Eliza Institute of Medical Research, Melbourne, Parkville, Victoria 3052, Australia;
- 5Cancer and Haematology Division, The Walter and Eliza Institute of Medical Research, Melbourne, Parkville, Victoria 3052, Australia
Abstract
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.
Keywords
- ERG
- ETS family transcription factors
- Gata2
- hematopoietic development
- hematopoietic stem cells
- Runx1
- self-renewal
Footnotes
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↵6 Corresponding author.
E-MAIL taoudi{at}wehi.edu.au; FAX 61-3-9347-0852.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.2009211.
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Supplemental material is available for this article.
- Received November 3, 2010.
- Accepted December 20, 2010.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press
