Changes in locus-specific V(D)J recombinase activity induced by immunoglobulin gene products during B cell development.
Changes in locus-specific V(D)J recombinase activity induced by immunoglobulin gene products during B cell development.
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DOI：
10.1084/jem.185.4.609
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发表时间：
1997-02-17
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影响因子：
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通讯作者：
Schlissel MS
中科院分区：
文献类型：
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作者：
Constantinescu A;Schlissel MS
V(D)J重组过程对于调节B细胞的发育和决定其最终抗原特异性至关重要。本研究通过监测V(D)J重组过程中产生的双链DNA断裂，直接评估了V(D)J重组酶的发育调控。该分析提供了免疫球蛋白重链和轻链位点在B细胞发育过程中确定的发育阶段的重组酶活性的测量。我们发现，一个完整的免疫球蛋白重链蛋白的表达伴随着V(D)J重组酶活性的急剧变化，从在前b细胞中主要在重链位点活跃到在前b细胞中仅限于轻链位点活跃。这种基因座特异性重组酶活性的转换导致免疫球蛋白重链基因座的等位基因排斥。等位基因排斥是由轻链位点的不同机制维持的。我们发现，未成熟但未成熟的B细胞已经表达了一种功能性的轻链蛋白，可以通过替换相同等位基因上的原始重排来进行持续的轻链基因重排。最后，我们发现发育调控的V(D)J重组靶向不受Eμ-myc转基因诱导的细胞周期强制快速转运的影响。
The process of V(D)J recombination is crucial for regulating the development of B cells and for determining their eventual antigen specificity. Here we assess the developmental regulation of the V(D)J recombinase directly, by monitoring the double-stranded DNA breaks produced in the process of V(D)J recombination. This analysis provides a measure of recombinase activity at immunoglobulin heavy and light chain loci across defined developmental stages spanning the process of B cell development. We find that expression of a complete immunoglobulin heavy chain protein is accompanied by a drastic change in the targeting of V(D)J recombinase activity, from being predominantly active at the heavy chain locus in pro-B cells to being exclusively restricted to the light chain loci in pre-B cells. This switch in locus-specific recombinase activity results in allelic exclusion at the immunoglobulin heavy chain locus. Allelic exclusion is maintained by a different mechanism at the light chain locus. We find that immature, but not mature, B cells that already express a functional light chain protein can undergo continued light chain gene rearrangement, by replacement of the original rearrangement on the same allele. Finally, we find that the developmentally regulated targeting of V(D)J recombination is unaffected by enforced rapid transit through the cell cycle induced by an Eμ-myc transgene.