The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/1/289/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 2, January 18, 1999 289-300

Articles

Positive and Negative Regulation of V(D)J Recombination by the E2A Proteins

Gretchen Bain*, William J. Romanow*, Karen Albers{ddagger}, Wendy L. Havran{ddagger}, and Cornelis Murre*

From the * Department of Biology, University of California San Diego, La Jolla, California 92093; and the {ddagger} Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

A key feature of B and T lymphocyte development is the generation of antigen receptors through the rearrangement and assembly of the germline variable (V), diversity (D), and joining (J) gene segments. However, the mechanisms responsible for regulating developmentally ordered gene rearrangements are largely unknown. Here we show that the E2A gene products are essential for the proper coordinated temporal regulation of V(D)J rearrangements within the T cell receptor (TCR) {gamma} and {delta} loci. Specifically, we show that E2A is required during adult thymocyte development to inhibit rearrangements to the {gamma} and {delta} V regions that normally recombine almost exclusively during fetal thymocyte development. The continued rearrangement of the fetal V{gamma}3 gene segment in E2A-deficient adult thymocytes correlates with increased levels of V{gamma}3 germline transcripts and increased levels of double-stranded DNA breaks at the recombination signal sequence bordering V{gamma}3. Additionally, rearrangements to a number of V{gamma} and V{delta} gene segments used predominately during adult development are significantly reduced in E2A-deficient thymocytes. Interestingly, at distinct stages of T lineage development, both the increased and decreased rearrangement of particular V{delta} gene segments is highly sensitive to the dosage of the E2A gene products, suggesting that the concentration of the E2A proteins is rate limiting for the recombination reaction involving these V{delta} regions.

Key Words: E2A • rearrangement • T cell receptor, {gamma} and {delta}

Address correspondence to Cornelis Murre, Department of Biology/MC 0366, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0366. Phone: 619-534-8796; Fax: 619-534-7550; E-mail: murre{at}biomail.ucsd.edu

Abbreviations used: bHLH, basic helix-loop-helix; LM, ligation-mediated; RAG, recombination activating gene; RSS, recombination signal sequence(s); RT, reverse transcription.


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