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Molecular and Cellular Biology, September 2004, p. 7491-7502, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7491-7502.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Decoding Hematopoietic Specificity in the Helix-Loop-Helix Domain of the Transcription Factor SCL/Tal-1

Thorsten M. Schlaeger,1,{dagger} Anna Schuh,2 Simon Flitter,3 Andreas Fisher,1,{ddagger} Hanna Mikkola,1 Stuart H. Orkin,1 Paresh Vyas,2 and Catherine Porcher3*

Department of Hematology/Oncology, Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts,1 MRC Molecular Haematology Unit,3 Department of Haematology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom2

Received 2 February 2004/ Returned for modification 26 March 2004/ Accepted 28 May 2004

The helix-loop-helix (HLH) domain is employed by many transcription factors that control cell fate choice in multiple developmental settings. Previously, we demonstrated that the HLH domain of the class II basic HLH (bHLH) protein SCL/Tal-1 is critical for hematopoietic specification. We have now identified residues in this domain that are essential for restoring hematopoietic development to SCL–/– embryonic stem cells and sufficient to convert a muscle-specific HLH domain to one able to rescue hematopoiesis. Most of these critical residues are distributed in the loop of SCL, with one in helix 2. This is in contrast to the case for MyoD, the prototype of class II bHLH proteins, where the loop seems to serve mainly as a linker between the two helices. Among the identified residues, some promote heterodimerization with the bHLH partners of SCL (E12/E47), while others, unimportant for this property, are still crucial for the biological function of SCL. Importantly, the residue in helix 2 specifically promotes interaction with a known partner of SCL, the LIM-only protein LMO2, a finding that strengthens genetic evidence that these proteins interact. Our data highlight the functional complexity of bHLH proteins, provide mechanistic insight into SCL function, and strongly support the existence of an active SCL/LMO2-containing multiprotein complex in early hematopoietic cells.

* Corresponding author. Mailing address: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom. Phone: 44 (0)1865 222 309. Fax: 44 (0)1865 222 500. E-mail: catherine.porcher{at}imm.ox.ac.uk.

{dagger} Present address: Cell and Molecular Technologies, Phillipsburg, NJ 08865.

{ddagger} Present address: Institute of Physiological Chemistry I, Theodor Boveri Institute, University of Würzburg, Würzburg, Germany.

Molecular and Cellular Biology, September 2004, p. 7491-7502, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7491-7502.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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