title: Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage.
abstract: 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.
authors.affiliation: Immune Disease Institute and Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Sergei B
authors.initials: SB
authors.lastname: Koralov
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Muljo
authors.forename: Gunther R
authors.initials: GR
authors.lastname: Galler
authors.forename: Azra
authors.initials: A
authors.lastname: Krek
authors.forename: Tirtha
authors.initials: T
authors.lastname: Chakraborty
authors.forename: Chryssa
authors.initials: C
authors.lastname: Kanellopoulou
authors.forename: Kari
authors.initials: K
authors.lastname: Jensen
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Cobb
authors.forename: Matthias
authors.initials: M
authors.lastname: Merkenschlager
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rajewsky
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
mesh_terms: 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
chemical_list: D020413:3' Untranslated Regions; D007136:Immunoglobulins; D035683:MicroRNAs; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases