Heterodimers between tissue-specific basic-helix-loop helix proteins and the gene products of E2A play major roles in determining tissue-specific ceil fate. To understand the broad role of E2A in development, we have generated E2A mutant mice following homologous recombination in embryonic stem cells. Homozygous mutant mice develop to full term without apparent abnormalities, but then display a high rate of postnatal death. The surviving mice show retarded postnatal growth. Detailed examination of hematopoiesis reveals that the homorygous mutant mice contain no B cells while other lineages including T cell, granulocyte, macrophage, and erythroid are intact. The block to B cell differentiation occurs priorto immunogiobuiin gene Dn-Jn rearrangement and the expression of the B lineage-specific marker 8220. Surprisingly, heterozygous embryos contain, on average, about half as many B cells as wild-type embryos, suggesting the existence of a counting mechanism that translates ievels of E2A into numbers of B cells.