The pre-B-cell receptor induces silencing of VpreB and [lamda]5 transcription

The pre-B-cell receptor (pre-BCR), composed of Ig heavy and surrogate light chain (SLC), signals pre-BII-cell proliferative expansion. We have investigated whether the pre-BCR also signals downregulation of the SLC genes (VpreB and lambda5), thereby limiting this expansion. We demonstrate that, as B...

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Veröffentlicht in:The EMBO journal 2005-11, Vol.24 (22), p.3895-3905
Hauptverfasser: Parker, Mathew J, Licence, Steve, Erlandsson, Lena, Galler, Gunther R, Chakalova, Lyubomira, Osborne, Cameron S, Morgan, Geoff, Fraser, Peter, Jumaa, Hassan, Winkler, Thomas H, Skok, Jane, Mårtensson, Inga-Lill
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Sprache:eng
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Zusammenfassung:The pre-B-cell receptor (pre-BCR), composed of Ig heavy and surrogate light chain (SLC), signals pre-BII-cell proliferative expansion. We have investigated whether the pre-BCR also signals downregulation of the SLC genes (VpreB and lambda5), thereby limiting this expansion. We demonstrate that, as BM cells progress from the pre-BI to large pre-BII-cell stage, there is a shift from bi- to mono-allelic lambda5 transcription, while the second allele is silenced in small pre-BII cells. A VpreB1-promoter-driven transgene shows the same pattern, therefore suggesting that VpreB1 is similarly regulated and thereby defines the promoter as a target for transcriptional silencing. Analyses of pre-BCR-deficient mice show a temporal delay in lambda5 downregulation, thereby demonstrating that the pre-BCR is essential for monoallelic silencing at the large pre-BII-cell stage. Our data also suggest that SLP-65 is one of the signaling components important for this process. Furthermore, the VpreB1/lambda5 alleles undergo dynamic changes with respect to nuclear positioning and heterochromatin association, thereby providing a possible mechanism for their transcriptional silencing.
ISSN:0261-4189
1460-2075
DOI:10.1038/sj.emboj.7600850