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Barndt, RJ, Dai, M and Zhuang, Y (2000) Functions of E2A-HEB heterodimers in T-cell development revealed by a dominant negative mutation of HEB. Mol. Cell. Biol. 20:6677-85


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.


PubMed PMC86175


Alleles; Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Lineage; DNA Nucleotidyltransferases; DNA-Binding Proteins/genetics; DNA-Binding Proteins/physiology; Dimerization; Gene Dosage; Gene Expression; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; Genes, T-Cell Receptor; Helix-Loop-Helix Motifs; Hematopoiesis; Humans; Leukopoiesis/genetics; Mice; Mice, Inbred C57BL; Mutagenesis; Phenotype; Receptors, Antigen, T-Cell, alpha-beta/genetics; T-Lymphocytes/cytology; TCF Transcription Factors; Thymus Gland; Transcription Factor 7-Like 1 Protein; Transcription Factors/genetics; Transcription Factors/physiology; Transgenes; VDJ Recombinases



Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status

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