title: The pre-B-cell receptor induces silencing of VpreB and lambda5 transcription.
abstract: 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.
authors.affiliation: Laboratory of Lymphocyte Signaling and Development, The Babraham Institute, Cambridge, UK.
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Parker
authors.forename: Steve
authors.initials: S
authors.lastname: Licence
authors.forename: Lena
authors.initials: L
authors.lastname: Erlandsson
authors.forename: Gunther R
authors.initials: GR
authors.lastname: Galler
authors.forename: Lyubomira
authors.initials: L
authors.lastname: Chakalova
authors.forename: Cameron S
authors.initials: CS
authors.lastname: Osborne
authors.forename: Geoff
authors.initials: G
authors.lastname: Morgan
authors.forename: Peter
authors.initials: P
authors.lastname: Fraser
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Winkler
authors.forename: Jane
authors.initials: J
authors.lastname: Skok
authors.forename: Inga-Lill
authors.initials: IL
authors.lastname: Mårtensson
mesh_terms: D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D004276:DNA, Satellite / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006570:Heterochromatin / Q000378:metabolism; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000378:metabolism; D054444:Immunoglobulin Light Chains, Surrogate; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054420:Pre-B Cell Receptors; D011401:Promoter Regions, Genetic; D011947:Receptors, Antigen, B-Cell; D014158:Transcription, Genetic; D019076:Transgenes
chemical_list: D004276:DNA, Satellite; D006570:Heterochromatin; D007147:Immunoglobulin Light Chains; D054444:Immunoglobulin Light Chains, Surrogate; D007135:Immunoglobulin Variable Region; D008562:Membrane Glycoproteins; D054420:Pre-B Cell Receptors; D011947:Receptors, Antigen, B-Cell