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J. Exp. Med.,
Volume 189, Number 2, January 18, 1999 289-300
By
From the * Department of Biology, University of California San Diego, La Jolla, California 92093;
and the 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) Department of Immunology, The Scripps Research Institute, La Jolla, California 92037
and 
loci. Specifically, we show that E2A is required during adult
thymocyte development to inhibit rearrangements to the and V regions that normally recombine almost exclusively during fetal thymocyte development. The continued rearrangement of the fetal V3 gene segment in E2A-deficient adult thymocytes correlates with increased levels of V3 germline transcripts and increased levels of double-stranded DNA breaks
at the recombination signal sequence bordering V3. Additionally, rearrangements to a number of V and V 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 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 regions.
and
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