B cell development proceeds through a defined set of cellular intermediates that give rise to mature cells. Current understanding of B cell development places EBF downstream of the transcription factors E2A and Pu.1 and signaling through the interleukin 7 receptor. EBF acts upstream of Pax5 which is considered to be the master regulator of B cell development. Contrary to this prevailing belief, Pax5 is incapable of rescuing the B cell deficiencies imposed by loss of E2A, Pu.1, IL-7R or EBF. However, ectopic expression of EBF partially restores the B cell defects imposed by loss of each of these factors. In this thesis we evaluated the role of EBF in B cell development. Loss of EBF function in B cell progenitors increases their ability to develop into non-B lineages. When expression of EBF is forced, it instructs multipotent and myeloid progenitors into the B lineage at the expense of myeloid and T development. We suggest that EBF effects this lineage decision by reducing the expression of C/EBPα and PU.1 to limit myeloid development and by lowering expression of GATA3 to limit T cell development. In order to address the cellular context where EBF can operate, we expressed EBF in E2A deficient myeloid progenitors. We demonstrated that EBF can redirect myeloid progenitors to the B lineage in the absence of E2A. Because EBF induces Pax5, we expressed EBF in Pax5-/- progenitors to determine the Pax5 independent roles of EBF. Strikingly, EBF blocked the generation of both myeloid and T lineage cells in the absence of Pax5. Because EBF is a Pax5 target, we hypothesize that a central role of Pax5 in the B lineage is to sustain EBF expression. The stable loop consisting of these two factors constitutes the core regulation of B lineage commitment. Although EBF promoted the development of B lineage cells in the absence of Pax5, they were incapable of maturation. Without EBF, Pax5 is capable of inducing the expression of CD19 and Ig-α, known Pax5 targets previously thought to depend on EBF. These results show that the principal regulators of the B lineage have both shared and separate roles
