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Molecular and Cellular Biology, September 2000, p. 6677-6685, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Functions of E2A-HEB Heterodimers in T-Cell Development Revealed by a Dominant Negative Mutation of HEB

Robert J. Barndt, Meifang Dai, and Yuan Zhuang*

Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710

Received 28 March 2000/Returned for modification 4 May 2000/Accepted 20 June 2000

Lymphocyte development and differentiation are regulated by the basic helix-loop-helix (bHLH) transcription factors encoded by the E2A and HEB genes. These bHLH proteins bind to E-box enhancers in the form of homodimers or heterodimers and, consequently, activate transcription of the target genes. E2A homodimers are the predominant bHLH proteins present in B-lineage cells and are shown genetically to play critical roles in B-cell development. E2A-HEB heterodimers, the major bHLH dimers found in thymocyte extracts, are thought to play a similar role in T-cell development. However, disruption of either the E2A or HEB gene led to only partial blocks in T-cell development. The exact role of E2A-HEB heterodimers and possibly the E2A and HEB homodimers in T-cell development cannot be distinguished in simple disruption analysis due to a functional compensation from the residual bHLH homodimers. To further define the function of E2A-HEB heterodimers, we generated and analyzed a dominant negative allele of HEB, which produces a physiological amount of HEB proteins capable of forming nonfunctional heterodimers with E2A proteins. Mice carrying this mutation show a stronger and earlier block in T-cell development than HEB complete knockout mice. The developmental block is specific to the alpha /beta T-cell lineage at a stage before the completion of V(D)J recombination at the TCRbeta gene locus. This defect is intrinsic to the T-cell lineage and cannot be rescued by expression of a functional T-cell receptor transgene. These results indicate that E2A-HEB heterodimers play obligatory roles both before and after TCRbeta gene rearrangement during the alpha /beta lineage T-cell development.

* Corresponding author. Mailing address: Department of Immunology, Box 3010, Duke University Medical Center, Durham, NC 27710. Phone: (919) 613-7824. Fax: (919) 684-8982. E-mail: yzhuang{at}acpub.duke.edu.

Molecular and Cellular Biology, September 2000, p. 6677-6685, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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