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From the Research Institute of Molecular Pathology, A-1030 Vienna, Austria

The formation of the pre-B cell receptor (BCR) corresponds to an important checkpoint in B cell development that selects pro-B (pre-BI) cells expressing a functionally rearranged immunoglobulin µ (Igµ) heavy chain protein to undergo the transition to the pre-B (pre-BII) cell stage. The pre-BCR contains, in addition to Igµ, the surrogate light chains 5 and VpreB and the signal transducing proteins Ig and Igβ. The absence of one of these pre-BCR components is known to arrest B cell development at the pre-BI cell stage. Disruption of the Pax5 gene, which codes for the B cell–specific activator protein (BSAP), also blocks adult B lymphopoiesis at the pre-BI cell stage. Moreover, expression of the mb-1 (Ig) gene and V_H-to-D_HJ_H recombination at the IgH locus are reduced in Pax5-deficient B lymphocytes 10- and 50-fold, respectively. Here we demonstrate that complementation of these deficiencies in pre-BCR components by expression of functionally rearranged Igµ and chimeric Igµ-Igβ transgenes fails to advance B cell development to the pre-BII cell stage in Pax5 (–/–) mice in contrast to RAG2 (–/–) mice. Furthermore, the pre-BCR is stably expressed on cultured pre-BI cells from Igµ transgenic, Pax5-deficient bone marrow, but is unable to elicit its normal signaling responses. In addition, the early developmental block is unlikely to be caused by the absence of a survival signal, as it could not be rescued by expression of a bcl2 transgene in Pax5-deficient pre-BI cells. Together, these data demonstrate that the absence of Pax5 arrests adult B lymphopoiesis at an early developmental stage that is unresponsive to pre-BCR signaling.

Key Words: B cell–specific activator protein • Pax5 • pro-B cell development • pre-B cell receptor • Igµ transgene

Claire Thévenin's present address is Department of Medical and Molecular Parasitology, New York University Medical Center, New York, NY 10016.

Abbreviations used: APC, allophycocyanin; BCR, B cell receptor; BSAP, B cell–specific activator protein; DNA-PK, DNA-dependent protein kinase; IgH, immunoglobulin heavy chain; RAG, recombination activating gene; scid, severe combined immune deficiency; TdT, terminal deoxynucleotidyl transferase.

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