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Published online on October 25, 2007, 10.1073/pnas.0707045104
PNAS | November 6, 2007 | vol. 104 | no. 45 | 17692-17697


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BIOLOGICAL SCIENCES / DEVELOPMENTAL BIOLOGY
Gata2, Fli1, and Scl form a recursively wired gene-regulatory circuit during early hematopoietic development

John E. Pimanda*,{dagger},{ddagger}, Katrin Ottersbach*, Kathy Knezevic*, Sarah Kinston*, Wan Y. I. Chan*, Nicola K. Wilson*, Josette-Renée Landry*, Andrew D. Wood*, Anja Kolb-Kokocinski§, Anthony R. Green*, David Tannahill§, Georges Lacaud, Valerie Kouskoff, and Berthold Göttgens*,{ddagger}

*Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; {dagger}Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney NSW 2052, Australia; §The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom; and Paterson Institute for Cancer Research, Manchester M20 4BX, United Kingdom

Edited by Mark T. Groudine, Fred Hutchinson Cancer Research Center, Seattle, WA, and approved August 28, 2007 (received for review July 26, 2007)

Conservation of the vertebrate body plan has been attributed to the evolutionary stability of gene-regulatory networks (GRNs). We describe a regulatory circuit made up of Gata2, Fli1, and Scl/Tal1 and their enhancers, Gata2-3, Fli1+12, and Scl+19, that operates during specification of hematopoiesis in the mouse embryo. We show that the Fli1+12 enhancer, like the Gata2-3 and Scl+19 enhancers, targets hematopoietic stem cells (HSCs) and relies on a combination of Ets, Gata, and E-Box motifs. We show that the Gata2-3 enhancer also uses a similar cluster of motifs and that Gata2, Fli1, and Scl are expressed in embryonic day-11.5 dorsal aorta where HSCs originate and in fetal liver where they multiply. The three HSC enhancers in these tissues and in ES cell-derived hemangioblast equivalents are bound by each of these transcription factors (TFs) and form a fully connected triad that constitutes a previously undescribed example of both this network motif in mammalian development and a GRN kernel operating during the specification of a mammalian stem cell.

hemangioblast | hematopoiesis | hematopoietic stem cell | network motif | transcription factor network

Author contributions: J.E.P. and B.G. designed research; J.E.P., K.O., K.K., S.K., W.Y.I.C., N.K.W., J.-R.L., A.D.W., A.K.-K., G.L., and V.K. performed research; J.E.P., K.O., K.K., S.K., W.Y.I.C., N.K.W., J.-R.L., A.K.-K., A.R.G., D.T., G.L., V.K., and B.G. analyzed data; and J.E.P. and B.G. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0707045104/DC1.

{ddagger}To whom correspondence may be addressed. E-mail: jpimanda{at}unsw.edu.au or bg200{at}cam.ac.uk

© 2007 by The National Academy of Sciences of the USA


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