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Commitment to the B-lymphoid lineage depends on the transcription factor Pax5

Abstract

The Pax5 gene encoding the B-cell-specific activator protein (BSAP) is expressed within the haematopoietic system exclusively in the B-lymphoid lineage, where it is required in vivo for progression beyond the pro-B-cell stage. However, Pax5 is not essential for in vitro propagation of pro-B cells in the presence of interleukin-7 and stromal cells. Here we show that pro-B cells lacking Pax5 are also incapable of in vitro B-cell differentiation unless Pax5 expression is restored by retroviral transduction. Pax5-/- pro-B cells are not restricted in their lineage fate, as stimulation with appropriate cytokines induces them to differentiate into functional macrophages, osteoclasts, dendritic cells, granulocytes and natural killer cells. As expected for a clonogenic haematopoietic progenitor with lymphomyeloid developmental potential, the Pax5-/- pro-B cell expresses genes of different lineage-affiliated programmes, and restoration of Pax5 activity represses this lineage-promiscuous transcription. Pax5 therefore plays an essential role in B-lineage commitment by suppressing alternative lineage choices.

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Figure 1: Pax5 is essential for in vitro differentiation of B lymphocytes.
Figure 2: Pax5-deficient pro-B cells are not restricted to the B-lymphoid lineage.
Figure 3: In vitro generation of macrophages and dendritic cells.
Figure 4: In vitro differentiation of osteoclasts and granulocytes.
Figure 5: Generation of mature NK cells.
Figure 6: Development of osteoclasts from Pax5-/- pro-B cells in vivo.
Figure 7: Lineage-promiscuous gene expression in Pax5-/- pro-B cells.

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Acknowledgements

We thank K. Matsuo and E. F. Wagner for c-fos-/- mice, ST2-TRANCE cells and advice concerning osteoclast biology; F. Alt for RAG2-/- mice; P. Steinlein and M. Dessing for FACS sorting and assistance with photography; and H. Beug for critical reading of the manuscript. This work was supported by the I.M.P. Vienna, by a grant from the Austrian Industrial Research Promotion Fund and by the Basel Institute for Immunology.

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Correspondence to Meinrad Busslinger.

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Nutt, S., Heavey, B., Rolink, A. et al. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature 401, 556–562 (1999). https://doi.org/10.1038/44076

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