Changes in Gene Expression Profiles in Developing B Cells of Murine Bone Marrow

Hoffmann, Reinhard; Seidl, Thomas; Neeb, Martin; Rolink, Antonius; Melchers, Fritz

doi:10.1101/gr.201501

Cited by 94 publications

(100 citation statements)

References 43 publications

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“…In addition, microarray analysis indicates that there are minimal differences in the gene expression profiles of Btk -/-and PLCc2 -/-pre-B cells derived from IL-7 cultures (unpublished observations). Expression of at least 90 genes is altered in response to BLNKdependent pre-BCR signals [54] and hundreds of genes differ between each stage of B cell development [55]. Thus, pre-B cells lacking either Btk or PLCc2 likely receive similar signals from the pre-BCR and IL-7 and reach a comparable stage of development in IL-7 cultures.…”

Section: Discussionmentioning

confidence: 99%

Btk and phospholipase Cγ2 can function independently during B cell development

et al. 2007

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The pre-BCR and the BCR regulate B cell development via a signalosome nucleated by the adaptor protein B cell linker protein (BLNK). Formation of this complex facilitates activation of phospholipase C (PLC) c2 by Bruton's tyrosine kinase (Btk). To determine whether Btk and PLCc2 also have separate functions, we generated Btk -/-PLCc2 -/-mice. They demonstrated a block in development at the pre-B stage and increased pre-BCR surface expression. This phenotype was more severe than that of Btk -/-or PLCc2 -/-mice. Although both Btk and PLCc2 were required for proliferation of splenic B cells in response to BCR cross-linking, they contributed differently to anti-IgM-induced phosphorylation of ERK. Btk -/-and PLCc2 -/-mice each had a reduced frequency of Igk-expressing B cells and impaired migration of pre-B cells towards stromal cellderived factor 1. However, the increase in pre-B cell malignancy that occurs in BLNK -/-mice in the absence of Btk was not observed in the absence of PLCc2. Thus, Btk and PLCc2 act both in concert and independently throughout B cell development. IntroductionSignals from the B cell antigen receptor (BCR) regulate multiple stages of B lymphopoiesis [1]. In pre-B cells, the pre-BCR signals for proliferation, allelic exclusion of the IgH locus, down-regulation of VpreB and k5 expression, and light chain rearrangement. The pre-BCR is predominantly intracellular and is believed to signal in a ligand-independent manner. The BCR is first expressed on the surface of immature B cells. Antigen encounter at this stage results in negative selection via deletion, anergy, or receptor editing. A tonic BCR signal is required for differentiation beyond the T2 stage in the periphery and survival of mature B cells. Mature B cells proliferate and differentiate upon stimulation with foreign antigen in the appropriate context. BCR and pre-BCR signaling is mediated by a signalosome composed of Syk, Bruton's tyrosine kinase (Btk), B cell linker protein (BLNK; also known as SLP65 and BASH), and phospholipase C (PLC) c2 [2-4]. Receptor cross-linking activates Syk, which phosphorylates the adaptor protein BLNK. Btk and PLCc2 bind to phosphorylated BLNK via their SH2 domains. Btk then phosphorylates and activates PLCc2, resulting in changes in intracellular Ca 2+ and the activation of protein kinase Cb. Btk can also mediate BCR-stimulated Ca 2+ flux [5] and B cell development [6] independently of its catalytic activity. Btk acts as an adaptor to recruit and activate phosphatidylinositol 4-phosphate 5-kinase (PIP5K) [5], which produces the substrate for PLCc2. Thus, Btk signals through PLCc2 directly, by phosphorylation, and indirectly, by increasing substrate availability.Loss of Btk function causes the human immunodeficiency X-linked agammaglobulinemia (XLA) [7,8], which is characterized by a block in B cell development at the pre-B stage. A similar disease results from

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Section: Discussionmentioning

confidence: 99%

Btk and phospholipase Cγ2 can function independently during B cell development

et al. 2007

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“…A second wave of recombination acting within the Ig light chain loci is initiated at the small resting pre-BII cell (8) stage with subsequent expression of Ig light chain genes in mice. A recent microarray study on gene expression profiling of early B cell development in mice indeed shows significant expression levels of Ig light chain genes notably in small resting pre-BII cells and-although to lesser extent-in large cycling pre-BII cells (29). The strong expression of Vpre-B and 5 surrogate light chain genes in the absence of Ig and Ig␣ light chain gene expression in the human CD10 ϩ CD19 ϩ CD20 Ϫ PBCs studied here diverges from the finding in mice (8,29) and suggests that human PBCs are more homogenous than their murine equivalent.…”

Section: Resultsmentioning

confidence: 99%

“…A recent microarray study on gene expression profiling of early B cell development in mice indeed shows significant expression levels of Ig light chain genes notably in small resting pre-BII cells and-although to lesser extent-in large cycling pre-BII cells (29). The strong expression of Vpre-B and 5 surrogate light chain genes in the absence of Ig and Ig␣ light chain gene expression in the human CD10 ϩ CD19 ϩ CD20 Ϫ PBCs studied here diverges from the finding in mice (8,29) and suggests that human PBCs are more homogenous than their murine equivalent. One explanation could be that in human PBCs-unlike in murine small resting pre-BII cells-Ig and Ig light chain genes are being rearranged but not expressed before the immature B cell stage.…”

Section: Resultsmentioning

confidence: 99%

Molecular portraits of B cell lineage commitment

Müschen

Lee

Zhou

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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In an attempt to characterize early B cell development including the commitment of progenitor cells to the B cell lineage, we generated and compared genomewide gene expression profiles of human hematopoietic stem cells (HSCs) and pre-B cells (PBCs) by using serial analysis of gene expression. From more than 100,000 serial analysis of gene expression tags collected from human CD34 ؉ HSCs and CD10 ؉ CD19 ؉ PBCs, 42,399 unique transcripts were identified in HSCs but only 16,786 in PBCs, suggesting that more than 60% of transcripts expressed in HSCs were silenced during or after commitment to the B cell lineage. On the other hand, mRNAs of pre-B cell receptor (pre-BCR)-associated genes are virtually missing in HSCs but account for more than 10% of the transcriptome of PBCs, which also show increased expression of apoptosis-related genes. Both concentration of the transcriptional repertoire on pre-BCRrelated genes together with marked up-regulation of apoptosis mediators in PBC might reflect selection for the expression of a functional pre-BCR within the bone marrow. Besides known regulator genes of early B cell development such as PAX5, E2A, and EBF, the most abundantly expressed genes in PBCs include ATM, PDGFRA, SIAH1, PIM2, C͞EBPB, WNT16, and TCL1, the role of which has not been established yet in early B cell development.

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“…(Fisher exact test; P=0.02). Concomitant with such tissue injury response, ascorbate increased pathways involved in stem cell maturation and maintenance (46,47).…”

Section: Gsea Of Wrn δHel/δhel Mice Treated With Ascorbatementioning

confidence: 99%

Vitamin C restores healthy aging in a mouse model for Werner syndrome

et al. 2009

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Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many phenotypic features of WS, including a prooxidant status and a shorter mean life span compared to wild-type animals. Here, we show that Wrn mutant mice also develop premature liver sinusoidal endothelial defenestration along with inflammation and metabolic syndrome. Vitamin C supplementation rescued the shorter mean life span of Wrn mutant mice and reversed several age-related abnormalities in adipose tissues and liver endothelial defenestration, genomic integrity, and inflammatory status. At the molecular level, phosphorylation of age-related stress markers like Akt kinase-specific substrates and the transcription factor NF-κB, as well as protein kinase Cδ and Hif-1α transcription factor levels, which are increased in the liver of Wrn mutants, were normalized by vitamin C. Vitamin C also increased the transcriptional regulator of lipid metabolism PPARα. Finally, microarray and gene set enrichment analyses on liver tissues revealed that vitamin C decreased genes normally up-regulated in human WS fibroblasts and cancers, and it increased genes involved in tissue injury response and adipocyte dedifferentiation in obese mice. Vitamin C did not have such effect on wild-type mice. These results indicate that vitamin C supplementation could be beneficial for patients with WS.

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Changes in Gene Expression Profiles in Developing B Cells of Murine Bone Marrow

Cited by 94 publications

References 43 publications

Btk and phospholipase Cγ2 can function independently during B cell development

Btk and phospholipase Cγ2 can function independently during B cell development

Molecular portraits of B cell lineage commitment

Vitamin C restores healthy aging in a mouse model for Werner syndrome

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