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Regulation of B cell fate specification and V H gene rearrangements by Ikaros
Author(s) -
REYNAUD Damien,
REDDY Karen,
SCHJERVEN Hilde,
SPOONER Chauncey,
BERTOLINO Eric,
SMALE Stephen T,
WINANDY Susan,
SINGH Harinder
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.844.7
Subject(s) - biology , gene , b cell , activator (genetics) , cd19 , transcription factor , genetics , pax5 , locus (genetics) , cd43 , microbiology and biotechnology , cell , antibody , cd20
Genetic analyses have established that the transcription factor Ikaros plays a critical role at the earliest step in B lymphopoiesis. We show that EBF expression in Ik−/− hematopoietic progenitors can rescue B cell development in vitro . The Ik−/− EBF‐rescued B cells are IL7Rα + , CD43 + and CD19 + and have turned on the expression of various early B cell genes including mb1, B29, λ5, VpreB, Pax5 and Aiolos . However, despite normal expression of Pax5 , these cells fail to properly repress the expression of Csf1r gene and as a result can differentiate into macrophages in the presence of M‐CSF. Moreover, Ik−/− pro‐B cells, in contrast to their wild type counterparts, express very low levels of the Rag and TdT genes and fail to undergo V‐to‐DJ rearrangements in the immunoglobulin heavy‐chain loci. We establish that Ikaros is a direct activator of the Rag locus in B‐lineage cells. Finally, we show that Ikaros is required for the proper rearrangement of the distal V H genes and controls both the accessibility of these genes and the compaction of the IgH locus. Collectively, our data reveals two unexpected functions of Ikaros proteins during early B cell differentiation: (i) as repressors of the myeloid program independently of Pax5 and (ii) as activators of Rag gene expression and V‐to‐DJ rearrangements.