Variegated Transcriptional Activation of the Immunoglobulin κ Locus in Pre-B Cells Contributes to the Allelic Exclusion of Light-Chain Expression

• Published in: Cell Vol. 118; no. 1; pp. 19 - 29
• Main Authors: Liang, Hong-Erh, Hsu, Lih-Yun, Cado, Dragana, Schlissel, Mark S
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09-07-2004
• Subjects: Alleles; Animals; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Biomarkers; Bone Marrow Cells - immunology; Cell Lineage; Cells, Cultured; Enhancer Elements, Genetic; Gene Dosage; Gene Expression Regulation, Developmental; Gene Frequency; Gene Rearrangement, B-Lymphocyte, Light Chain - immunology; Genes, Immunoglobulin; Genes, Reporter; Green Fluorescent Proteins; Heterozygote; Immunoglobulin kappa-Chains - genetics; Immunoglobulin Light Chains - genetics; Immunoglobulin Light Chains - immunology; Immunoglobulin Variable Region; Luminescent Proteins - metabolism; Mice; Mice, Mutant Strains; Promoter Regions, Genetic; Recombination, Genetic; Spleen - cytology; Stem Cells - immunology; Transcriptional Activation
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2004.06.019

Regulated gene rearrangement is thought to underlie allelic exclusion, the observation that an individual B cell expresses only a single immunoglobulin molecule. Previous data has implicated transcriptional activation of rearranging loci in the regulation of their accessibility to the V(D)J recombinase. Using homologous recombination in ES cells, we have generated “knockin” mice which express a GFP cDNA from an unrearranged immunoglobulin κ light-chain allele. Surprisingly, we find that only a small fraction of κ alleles are highly transcribed in a population of pre-B cells, that such transcription is monoallelic, and that these highly transcribed alleles account for the vast majority of κ light-chain gene rearrangement. These data lead us to suggest that probabilistic enhancer activation and allelic competition are part of the mechanism of κ locus allelic exclusion and may be a general mechanism contributing to cellular differentiation during development.