scholarly journals PU.1 Regulates Ig Light Chain Transcription and Rearrangement in Pre-B Cells during B Cell Development

2017 ◽  
Vol 198 (4) ◽  
pp. 1565-1574 ◽  
Author(s):  
Carolina R. Batista ◽  
Stephen K. H. Li ◽  
Li S. Xu ◽  
Lauren A. Solomon ◽  
Rodney P. DeKoter
Keyword(s):  
B Cells ◽  
B Cell ◽  
Light Chain ◽  
Cell Development ◽  
B Cell Development

scholarly journals Changes in Locus-specific V(D)J Recombinase Activity Induced by Immunoglobulin Gene Products during B Cell Development

1997 ◽  
Vol 185 (4) ◽  
pp. 609-620 ◽  
Author(s):  
Andrei Constantinescu ◽  
Mark S. Schlissel
Keyword(s):  
B Cells ◽  
B Cell ◽  
Heavy Chain ◽  
Light Chain ◽  
Immunoglobulin Heavy Chain ◽  
Cell Development ◽  
B Cell Development ◽  
Allelic Exclusion ◽  
Chain Locus ◽  
Heavy Chain Locus

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.

Enforced BCL6 Expression Inhibits B Cell Development in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1535-1535
Author(s):  
Davide F. Robbiani ◽  
Kaity Colon ◽  
Kruti Naik ◽  
Helen Nickerson ◽  
Maurizio Affer ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Light Chain ◽  
Germinal Center ◽  
Regulatory Elements ◽  
Cell Development ◽  
B Cell Development ◽  
Kappa Light Chain

Abstract The B-Cell Lymphoma 6 (BCL6) gene encodes for a zinc finger motifs containing transcriptional repressor that is frequently dysregulated by chromosomal translocations in germinal center lymphomas. A putative protooncogene, its transforming ability in vivo was reported in I-mu-HA-BCL6 knock-in mice by Cattoretti et al last year. We also tested this assumption in transgenic mice expressing BCL6 in B cells under the control of kappa light chain regulatory elements. We replaced the murine C-kappa locus with the 16kb human BCL6 genomic locus in a construct containing the murine kappa light chain regulatory elements (Vk, EiK, 3′RR). While control transgenics were readily obtained (5/32 founders), only 3/68 founders were positive for the BCL6 transgene, of which only one (bearing a single copy of the transgene) was able to transmit the transgene to its progeny, thus suggesting embryonal toxicity of exogenous BCL6. In the bone marrow, flow cytometry revealed a nearly complete block of B cell development at the pro-B to pre-B transition. This was also the stage at which we first detected expression of EGFP in control reporter mice that were generated in parallel. Spleens of transgenic mice weighed about 50% of control spleens and less than 5% of splenocytes were CD19+ B cells. These were IgM high, IgD intermediate, corresponding to an immature B cell phenotype. Lymph nodes were smaller and B cells barely detected. Peyers’ patches were not visible. Combined, our analysis of 6–8 weeks old VkHABCL6 transgenic mice reveals that enforced expression of BCL6 early in development results in a profound block of B lymphocyte differentiation. How transgenic BCL6 modulates this effect at the transcriptional level remains to be investigated. To test the oncogenic potential of BCL6 in B cells, it will be interesting to precisely turn on this gene in the germinal center.

scholarly journals Ddx3xregulates B-cell development and light chain recombination in mice

2018 ◽  
Author(s):  
Ke Liu ◽  
Jasmine Tuazon ◽  
Erik P. Karmele ◽  
Durga Krishnamurthy ◽  
Thomas Perlor ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Light Chain ◽  
Rna Helicase ◽  
Cell Development ◽  
B Cell Development ◽  
Lymphoid Tissues ◽  
Immunoglobulin Kappa ◽  
Dead Box

AbstractDdx3xencodes a DEAD box RNA helicase implicated in antiviral immunity and tumorigenesis. We find that hematopoieticDdx3xdeficiency inVav1-Cremice (ΔDdx3x) results in altered leukocyte composition of secondary lymphoid tissues, including a marked reduction in mature B cells. This paucity of peripheral B cells is associated with deficits in B-cell development in the bone marrow, including reduced frequencies of small pre-B cells. Bone marrow chimera experiments reveal a B-cell intrinsic effect ofDdx3xdeletion. Mechanistically, ΔDdx3xsmall pre-B cells exhibit lower expression ofBrwd1, a histone reader that restricts recombination at the immunoglobulin kappa (Igk)locus. In fact, the B-cell deficits in ΔDdx3xmice resemble those ofBrwd1mutant mice, and both strains of mice exhibit defectiveIgkrearrangement in small pre-B cells. The contribution ofDdx3xtoBrwd1expression and light chain rearrangement constitutes the first evidence of a role for an RNA helicase in promoting B-cell development.

Loss of IP3 Receptor–Mediated Ca2+ Release in Mouse B Cells Results in Abnormal B Cell Development and Function

2017 ◽  
Vol 199 (2) ◽  
pp. 570-580 ◽  
Author(s):  
Huayuan Tang ◽  
Hong Wang ◽  
Qingsong Lin ◽  
Feifei Fan ◽  
Fei Zhang ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Ip3 Receptor ◽  
And Function

scholarly journals Differential Regulation of Mouse B Cell Development by Transforming Growth Factor β1

2002 ◽  
Vol 9 (2) ◽  
pp. 86-95 ◽  
Author(s):  
Denise A. Kaminski ◽  
John J. Letterio ◽  
Peter D. Burrows
Keyword(s):  
B Cells ◽  
Growth Factor ◽  
B Cell ◽  
Transforming Growth Factor ◽  
Plasma Cells ◽  
Population Analysis ◽  
Cell Development ◽  
B Cell Development

Transforming growth factor β (TGFβ) can inhibit thein vitroproliferation, survival and differentiation of B cell progenitors, mature B lymphocytes and plasma cells. Here we demonstrate unexpected, age-dependent reductions in the bone marrow (BM) B cell progenitors and immature B cells in TGFβ1-/-mice. To evaluate TGFβ responsiveness during normal B lineage development, cells were cultured in interleukin 7 (IL7)±TGFβ. Picomolar doses of TGFβ1 reduced pro-B cell recoveries at every timepoint. By contrast, the pre-B cells were initially reduced in number, but subsequently increased compared to IL7 alone, resulting in a 4-fold increase in the growth rate for the pre-B cell population. Analysis of purified BM sub-populations indicated that pro-B cells and the earliest BP1-pre-B cells were sensitive to the inhibitory effects of TGFβ1. However, the large BP1+pre-B cells, although initially reduced, were increased in number at days 5 and 7 of culture. These results indicate that TGFβ1 is important for normal B cell developmentin vivo, and that B cell progenitors are differentially affected by the cytokine according to their stage of differentiation.

scholarly journals Ligand-independent Signaling Functions for the B Lymphocyte Antigen Receptor and Their Role in Positive Selection during B Lymphopoiesis

2001 ◽  
Vol 194 (11) ◽  
pp. 1583-1596 ◽  
Author(s):  
Gregory Bannish ◽  
Ezequiel M. Fuentes-Pananá ◽  
John C. Cambier ◽  
Warren S. Pear ◽  
John G. Monroe
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Antigen Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
B Lymphopoiesis ◽  
Biologically Relevant ◽  
Developmental Progression

Signal transduction through the B cell antigen receptor (BCR) is determined by a balance of positive and negative regulators. This balance is shifted by aggregation that results from binding to extracellular ligand. Aggregation of the BCR is necessary for eliciting negative selection or activation by BCR-expressing B cells. However, ligand-independent signaling through intermediate and mature forms of the BCR has been postulated to regulate B cell development and peripheral homeostasis. To address the importance of ligand-independent BCR signaling functions and their regulation during B cell development, we have designed a model that allows us to isolate the basal signaling functions of immunoglobulin (Ig)α/Igβ-containing BCR complexes from those that are dependent upon ligand-mediated aggregation. In vivo, we find that basal signaling is sufficient to facilitate pro-B → pre-B cell transition and to generate immature/mature peripheral B cells. The ability to generate basal signals and to drive developmental progression were both dependent on plasma membrane association of Igα/Igβ complexes and intact immunoregulatory tyrosine activation motifs (ITAM), thereby establishing a correlation between these processes. We believe that these studies are the first to directly demonstrate biologically relevant basal signaling through the BCR where the ability to interact with both conventional as well as nonconventional extracellular ligands is eliminated.

scholarly journals An evolutionarily conserved program of B-cell development and activation in zebrafish

Blood ◽  
2013 ◽  
Vol 122 (8) ◽  
pp. e1-e11 ◽  
Author(s):  
Dawne M. Page ◽  
Valerie Wittamer ◽  
Julien Y. Bertrand ◽  
Kanako L. Lewis ◽  
David N. Pratt ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Transition Point ◽  
Cell Development ◽  
B Cell Development ◽  
Key Points ◽  
Evolutionarily Conserved

Key Points B cells appear in zebrafish by 3 weeks of development, supporting previous data that this is the transition point to adult hematopoiesis. Shifting sites of B-cell development likely occur in all jawed vertebrates.

scholarly journals Transcription factors of the alternative NF-κB pathway are required for germinal center B-cell development

2016 ◽  
Vol 113 (32) ◽  
pp. 9063-9068 ◽  
Author(s):  
Nilushi S. De Silva ◽  
Michael M. Anderson ◽  
Amanda Carette ◽  
Kathryn Silva ◽  
Nicole Heise ◽  
...  
Keyword(s):  
Transcription Factors ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Alternative Pathway ◽  
Cell Development ◽  
B Cell Development ◽  
Cell Surface Receptor ◽  
Signaling Cascade

The NF-κB signaling cascade relays external signals essential for B-cell growth and survival. This cascade is frequently hijacked by cancers that arise from the malignant transformation of germinal center (GC) B cells, underscoring the importance of deciphering the function of NF-κB in these cells. The NF-κB signaling cascade is comprised of two branches, the canonical and alternative NF-κB pathways, mediated by distinct transcription factors. The expression and function of the transcription factors of the alternative pathway, RELB and NF-κB2, in late B-cell development is incompletely understood. Using conditional deletion of relb and nfkb2 in GC B cells, we here report that ablation of both RELB and NF-κB2, but not of the single transcription factors, resulted in the collapse of established GCs. RELB/NF-κB2 deficiency in GC B cells was associated with impaired cell-cycle entry and reduced expression of the cell-surface receptor inducible T-cell costimulator ligand that promotes optimal interactions between B and T cells. Analysis of human tonsillar tissue revealed that plasma cells and their precursors in the GC expressed high levels of NF-κB2 relative to surrounding lymphocytes. Accordingly, deletion of nfkb2 in murine GC B cells resulted in a dramatic reduction of antigen-specific antibody-secreting cells, whereas deletion of relb had no effect. These results demonstrate that the transcription factors of the alternative NF-κB pathway control distinct stages of late B-cell development, which may have implications for B-cell malignancies that aberrantly activate this pathway.

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