Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage.
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 approximately 92 signature in the 3'UTRs of genes upregulated in Dicer-deficient pro-B cells; a top miR-17 approximately 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 kappa chain loci, but increased sterile transcription and usage of D(H) elements of the DSP family in IgH, and increased N sequence addition in Igkappa due to deregulated transcription of the terminal deoxynucleotidyl transferase gene.
Koralov
Sergei B
SB
Immune Disease Institute and Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Muljo
Stefan A
SA
Galler
Gunther R
GR
Krek
Azra
A
Chakraborty
Tirtha
T
Kanellopoulou
Chryssa
C
Jensen
Kari
K
Cobb
Bradley S
BS
Merkenschlager
Matthias
M
Rajewsky
Nikolaus
N
Rajewsky
Klaus
K
D020413:3' Untranslated Regions / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000916:Antibody Diversity; D001402:B-Lymphocytes / Q000166:cytology*; D015152:Blotting, Northern; D002470:Cell Survival; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D015322:Gene Rearrangement, B-Lymphocyte; D007136:Immunoglobulins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III; D013047:Specific Pathogen-Free Organisms
D020413:3' Untranslated Regions; D007136:Immunoglobulins; D035683:MicroRNAs; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases