Abstract
The transcription factor Ikaros is essential for B cell development. However, its molecular functions in B cell fate specification and commitment have remained elusive. We show here that the transcription factor EBF restored the generation of CD19+ pro–B cells from Ikaros-deficient hematopoietic progenitors. Notably, these pro–B cells, despite having normal expression of the transcription factors EBF and Pax5, were not committed to the B cell fate. They also failed to recombine variable gene segments at the immunoglobulin heavy-chain locus. Ikaros promoted heavy-chain gene rearrangements by inducing expression of the recombination-activating genes as well as by controlling accessibility of the variable gene segments and compaction of the immunoglobulin heavy-chain locus. Thus, Ikaros is an obligate component of a network that regulates B cell fate commitment and immunoglobulin heavy-chain gene recombination.
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Acknowledgements
We thank members of the Singh lab for suggestions and comments. Plasmids pEBB-Rag1 and pEBB-Rag2 were gifts from D.G. Schatz (Yale University); Pax5−/− pro–B cells were a gift from M. Busslinger (Research Institute of Molecular Pathology). Supported by the Irvington Institute Fellowship program of the Cancer Research Institute (I.A.D.), the Research Council of Norway (H.Sc.), the China Scholarship Council (Z.C.), the National Institutes of Health (R01 DK43726 to S.T.S.) and the Howard Hughes Medical Institute (H.Si.).
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D.R. designed and did the experiments, analyzed data and wrote the manuscript; I.A.D. and K.L.R. contributed immuno-FISH data; H.Sc. did EMSA; Z.C. helped with RT-PCR analysis; E.B., S.T.S. and S.W. provided experimental advice; and H.Si. supervised the research and wrote the manuscript.
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Reynaud, D., A Demarco, I., L Reddy, K. et al. Regulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros. Nat Immunol 9, 927–936 (2008). https://doi.org/10.1038/ni.1626
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DOI: https://doi.org/10.1038/ni.1626
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