Early function of Pax5 (BSAP) before the pre-B cell receptor stage of B lymphopoiesis.
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 mu (Igmu) heavy chain protein to undergo the transition to the pre-B (pre-BII) cell stage. The pre-BCR contains, in addition to Igmu, the surrogate light chains lambda5 and VpreB and the signal transducing proteins Igalpha and Igbeta. 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 (Igalpha) gene and VH-to-DHJH recombination at the IgH locus are reduced in Pax5-deficient B lymphocytes approximately 10- and approximately 50-fold, respectively. Here we demonstrate that complementation of these deficiencies in pre-BCR components by expression of functionally rearranged Ig mu and chimeric Igmu-Igbeta 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 Igmu 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.
Research Institute of Molecular Pathology, A-1030 Vienna, Austria.
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Thévenin
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Nutt
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Busslinger
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D007148:Immunoglobulin mu-Chains / Q000235:genetics; D019891:Leukopoiesis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D051757:PAX5 Transcription Factor; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D007148:Immunoglobulin mu-Chains; D009687:Nuclear Proteins; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; C497282:Pax5 protein, mouse; D011947:Receptors, Antigen, B-Cell; D014157:Transcription Factors