ESSENTIAL FUNCTIONS OF PAX5 (BSAP) IN PRO-B CELL-DEVELOPMENT - DIFFERENCE BETWEEN FETAL AND ADULT-B LYMPHOPOIESIS AND REDUCED V-TO-DJ RECOMBINATION AT THE IGH LOCUS

The Pax5 gene coding for the transcription factor BSAP has an essentia l role in B lymphopoiesis and midbrain development. Here we present a detailed analysis of the B-cell phenotype of Pax5 mutant mice that rev ealed a differential dependency of fetal and adult B lymphopoiesis on this transcriptional regulator. B-cell development is arrested in the bone marrow at the early pro-B (pre-BI) cell stage, which is character ized by expression of the early markers c-kit, CD43, lambda 5, V-preB, and HSA and the absence of the later markers CD25 and BP-1. These pre -BI cells fail to express the BSAP target gene CD19 and are capable of long-term proliferation in vitro in the presence of stromal cells and IL-7. B-lymphoid progenitors could not be detected in the fetal liver of Pax5 mutant embryos. However, Pax5-deficient fetal liver cells gav e rise to the development of pre-BI cells in bone marrow on transplant ation into lethally irradiated mice. These data indicate different fun ctions of Pax5 in the distinctive microenvironments of fetal liver and adult bone marrow. As shown by PCR analyses, the pre-BI cells in Pax5 -deficient bone marrow have undergone D-H-to-J(H) rearrangement of the immunoglobulin heavy-chain locus at normal frequency. In contrast, V- H-to-D(H)J(H) rearrangements were reduced similar to 50-fold in Pax5-d eficient pre-BI cells, suggesting a role for Pax5 in the developmental pathway controlling V-to-DJ recombination.