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Dicer Ablation Affects Antibody Diversity and Cell Survival in the B Lymphocyte Lineage

2008; Cell Press; Volume: 132; Issue: 5 Linguagem: Inglês

10.1016/j.cell.2008.02.020

1097-4172

Sergei B. Koralov, Stefan A. Muljo, Gunther R. Galler, Azra Krek, Tirtha Chakraborty, Chryssa Kanellopoulou, Kari Jensen, Bradley S. Cobb, Matthias Merkenschlager, Nikolaus Rajewsky, Klaus Rajewsky,

RNA Interference and Gene Delivery

To explore the role of Dicer-dependent control mechanisms in B lymphocyte development, we ablated this enzyme in early B cell progenitors. This resulted in a developmental block at the pro- to pre-B cell transition. Gene-expression profiling revealed a miR-17∼92 signature in the 3′UTRs of genes upregulated in Dicer-deficient pro-B cells; a top miR-17∼92 target, the proapoptotic molecule Bim, was highly upregulated. Accordingly, B cell development could be partially rescued by ablation of Bim or transgenic expression of the prosurvival protein Bcl-2. This allowed us to assess the impact of Dicer deficiency on the V(D)J recombination program in developing B cells. We found intact Ig gene rearrangements in immunoglobulin heavy (IgH) and κ chain loci, but increased sterile transcription and usage of DH elements of the DSP family in IgH, and increased N sequence addition in Igκ due to deregulated transcription of the terminal deoxynucleotidyl transferase gene.