E2A PROTEINS ARE REQUIRED FOR PROPER B-CELL DEVELOPMENT AND INITIATION OF IMMUNOGLOBULIN GENE REARRANGEMENTS

E12 and E47 are two helix-loop-helix transcription factors that arise by alternative splicing of the E2A gene. Both have been implicated in the regulation of immunoglobulin gene expression. We have now generate d E2A (-/-) mice by gene targeting. E2A-null mutant mice fail to gener ate mature B cells. The arrest of B cell development occurs at an earl y stage, since no immunoglobulin DJ rearrangements can be detected in homozygous mutant mice. While immunoglobulin germline I-mu RAG-1, mb-1 , CD19, and lambda 5 transcripts are dramatically reduced in fetal liv ers of E2A (-/-) mice, B29 and mu degrees transcripts are present, but at lower levels. In addition, we show that Pax-5 transcripts are sign ificantly reduced in fetal livers of E2A (-/-) mice. These data sugges t a crucial role for E2A products as central regulators in early B cel l differentiation.