Abstract
The chromatin regulator Aiolos and the transcriptional coactivator OBF-1 have been implicated in regulating aspects of B cell maturation and activation. Mice lacking either of these factors have a largely normal early B cell development. However, when both factors are eliminated simultaneously a block is uncovered at the transition between pre-B and immature B cells, indicating that these proteins exert a critical function in developing B lymphocytes. In mice deficient for Aiolos and OBF-1, the numbers of immature B cells are reduced, small pre-BII cells are increased and a significant impairment in immunoglobulin light chain DNA rearrangement is observed. We identified genes whose expression is deregulated in the pre-B cell compartment of these mice. In particular, we found that components of the pre-BCR, such as the surrogate light chain genes λ5 and VpreB, fail to be efficiently silenced in double-mutant mice. Strikingly, developmentally regulated nuclear repositioning of the λ5 gene is impaired in pre-B cells lacking OBF-1 and Aiolos. These studies uncover a novel role for OBF-1 and Aiolos in controlling the transcription and nuclear organization of genes involved in pre-BCR function.
Highlights
The developmental fate of B lymphocytes is tightly controlled by a large number of transcription factors [1,2,3]
Transition from small pre-BII cells to immature B cells is impaired in Aiolos/OBF-1 double mutant mice
We have shown previously that the number of mature resting B cells is only marginally altered in the single-mutant mice, but is reduced several-fold in Aiolos2/2/OBF-12/2 mice [21]
Summary
The developmental fate of B lymphocytes is tightly controlled by a large number of transcription factors [1,2,3]. Rearrangement of the immunoglobulin heavy chain (IgH: mHC) takes place at the pre-BI cell stage and its functionality is checked at the subsequent pre-BII cell stage [4,5] At this stage, the heavy chain associates with the surrogate light chain (SLC), encoded by the VpreB and l5 genes, to form the pre-B cell receptor (pre-BCR), which is displayed at the cell surface. A small number of the surviving cells, possibly having a lower level of BCR signaling [10], differentiate into the naıve and sessile marginal zone B (MZB) cells, while the majority of the surviving transitional B cells become naıve follicular B cells These long-lived cells circulate through the follicles of the spleen, lymph nodes and the bone marrow
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