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PMID: 9705955 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Early function of Pax5 (BSAP) before the pre-B cell receptor stage of B lymphopoiesis.

The Journal of experimental medicine ·Vol. 188 ·No. 4 ·1998-08-17 ·Pages 735-44

Thévenin C, Nutt SL, Busslinger M

Abstract

The formation of the pre-B cell receptor (BCR) corresponds to an important checkpoint in B cell development that selects pro-B (pre-BI) cells expressing a functionally rearranged immunoglobulin mu (Igmu) heavy chain protein to undergo the transition to the pre-B (pre-BII) cell stage. The pre-BCR contains, in addition to Igmu, the surrogate light chains lambda5 and VpreB and the signal transducing proteins Igalpha and Igbeta. The absence of one of these pre-BCR components is known to arrest B cell development at the pre-BI cell stage. Disruption of the Pax5 gene, which codes for the B cell-specific activator protein (BSAP), also blocks adult B lymphopoiesis at the pre-BI cell stage. Moreover, expression of the mb-1 (Igalpha) gene and VH-to-DHJH recombination at the IgH locus are reduced in Pax5-deficient B lymphocytes approximately 10- and approximately 50-fold, respectively. Here we demonstrate that complementation of these deficiencies in pre-BCR components by expression of functionally rearranged Ig mu and chimeric Igmu-Igbeta transgenes fails to advance B cell development to the pre-BII cell stage in Pax5 (-/-) mice in contrast to RAG2 (-/-) mice. Furthermore, the pre-BCR is stably expressed on cultured pre-BI cells from Igmu transgenic, Pax5-deficient bone marrow, but is unable to elicit its normal signaling responses. In addition, the early developmental block is unlikely to be caused by the absence of a survival signal, as it could not be rescued by expression of a bcl2 transgene in Pax5-deficient pre-BI cells. Together, these data demonstrate that the absence of Pax5 arrests adult B lymphopoiesis at an early developmental stage that is unresponsive to pre-BCR signaling.

MeSH Terms
Animals B-Lymphocytes/cytology,physiology Cells, Cultured DNA-Binding Proteins/genetics,physiology Hematopoietic Stem Cells/cytology,physiology Humans Immunoglobulin mu-Chains/genetics Leukopoiesis/physiology Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Nuclear Proteins/genetics,physiology PAX5 Transcription Factor Receptors, Antigen, B-Cell/physiology Signal Transduction Transcription Factors
Chemicals
DNA-Binding Proteins Immunoglobulin mu-Chains Nuclear Proteins PAX5 Transcription Factor PAX5 protein, human Pax5 protein, mouse Receptors, Antigen, B-Cell Transcription Factors
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Thévenin C
Research Institute of Molecular Pathology, A-1030 Vienna, Austria.
Nutt S L
Busslinger M
References (57)
57 references, click to expand
  1. The expression of Vpre-B/lambda 5 surrogate light chain in early bone marrow precursor B cells of normal and B cell-deficient mutant mice.
    Cell. 1994 Apr 8;77(1):133-43 PMID: 8156589
  2. Bcl-2 expression promotes B- but not T-lymphoid development in scid mice.
    Nature. 1994 Mar 31;368(6470):457-60 PMID: 8133891
  3. Influence of immunoglobulin heavy- and light-chain expression on B-cell differentiation.
    Genes Dev. 1994 May 1;8(9):1043-57 PMID: 7926786
  4. Temporal differences in the activation of three classes of non-transmembrane protein tyrosine kinases following B-cell antigen receptor surface engagement.
    Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9524-8 PMID: 7524079
  5. IL-2 receptor alpha chain (CD25, TAC) expression defines a crucial stage in pre-B cell development.
    Int Immunol. 1994 Aug;6(8):1257-64 PMID: 7526894
  6. Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP.
    Cell. 1994 Dec 2;79(5):901-12 PMID: 8001127
  7. Precursor B cells of mouse bone marrow express two different complexes with the surrogate light chain on the surface.
    Eur J Immunol. 1995 Feb;25(2):446-50 PMID: 7875207
  8. Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation.
    Cell. 1995 Mar 10;80(5):813-23 PMID: 7889575
  9. The role of Ig beta in precursor B cell transition and allelic exclusion.
    Science. 1995 Apr 21;268(5209):408-11 PMID: 7716544
  10. Development of B cells in scid mice with immunoglobulin transgenes: implications for the control of V(D)J recombination.
    Immunity. 1995 Jun;2(6):607-16 PMID: 7796294
  11. Transmembrane signaling by antigen receptors of B and T lymphocytes.
    Curr Opin Cell Biol. 1995 Apr;7(2):163-75 PMID: 7612267
  12. The cytoplasmic domains of immunoglobulin (Ig) alpha and Ig beta can independently induce the precursor B cell transition and allelic exclusion.
    J Exp Med. 1995 Nov 1;182(5):1389-94 PMID: 7595209
  13. Internalization of B cell and pre-B cell receptors is regulated by tyrosine kinase and phosphatase activities.
    Eur J Immunol. 1995 Oct;25(10):2757-64 PMID: 7589068
  14. Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk.
    Nature. 1995 Nov 16;378(6554):298-302 PMID: 7477352
  15. Syk tyrosine kinase required for mouse viability and B-cell development.
    Nature. 1995 Nov 16;378(6554):303-6 PMID: 7477353
  16. Regulation of an early developmental checkpoint in the B cell pathway by Ig beta.
    Science. 1996 Apr 19;272(5260):411-4 PMID: 8602530
  17. Frequent aberrant immunoglobulin gene rearrangements in pro-B cells revealed by a bcl-xL transgene.
    Immunity. 1996 Mar;4(3):291-9 PMID: 8624819
  18. Clonal selection and learning in the antibody system.
    Nature. 1996 Jun 27;381(6585):751-8 PMID: 8657279
  19. Composition and function of T-cell receptor and B-cell receptor complexes on precursor lymphocytes.
    Curr Opin Immunol. 1996 Apr;8(2):181-90 PMID: 8725941
  20. A prematurely expressed Ig(kappa) transgene, but not V(kappa)J(kappa) gene segment targeted into the Ig(kappa) locus, can rescue B cell development in lambda5-deficient mice.
    Immunity. 1996 Sep;5(3):229-39 PMID: 8808678
  21. The SCID but not the RAG-2 gene product is required for S mu-S epsilon heavy chain class switching.
    Immunity. 1996 Oct;5(4):319-30 PMID: 8885865
  22. Early expression of Ig mu chain from a transgene significantly reduces the duration of the pro-B stage but does not affect the small pre-B stage.
    Int Immunol. 1996 Aug;8(8):1319-28 PMID: 8918701
  23. Surrogate or conventional light chains are required for membrane immunoglobulin mu to activate the precursor B cell transition.
    J Exp Med. 1996 Nov 1;184(5):2025-30 PMID: 8920890
  24. Identification of the earliest B lineage stage in mouse bone marrow.
    Immunity. 1996 Dec;5(6):527-35 PMID: 8986713
  25. Down-regulation of terminal deoxynucleotidyl transferase by Ig heavy chain in B lineage cells.
    J Immunol. 1997 Feb 1;158(3):1133-8 PMID: 9013952
  26. Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus.
    Genes Dev. 1997 Feb 15;11(4):476-91 PMID: 9042861
  27. Constitutive Bcl-2 expression during immunoglobulin heavy chain-promoted B cell differentiation expands novel precursor B cells.
    Immunity. 1997 Jan;6(1):23-33 PMID: 9052834
  28. The immunoglobulin (Ig)alpha and Igbeta cytoplasmic domains are independently sufficient to signal B cell maturation and activation in transgenic mice.
    J Exp Med. 1997 May 19;185(10):1753-8 PMID: 9151700
  29. Changes in the V(H) gene repertoire of developing precursor B lymphocytes in mouse bone marrow mediated by the pre-B cell receptor.
    Immunity. 1997 Sep;7(3):357-68 PMID: 9324356
  30. Monoclonal antibodies specific for murine IgM I. Characterization of antigenic determinants on the four constant domains of the mu heavy chain.
    Eur J Immunol. 1984 Jun;14(6):534-42 PMID: 6203757
  31. Introduction of a mu immunoglobulin gene into the mouse germ line: specific expression in lymphoid cells and synthesis of functional antibody.
    Cell. 1984 Oct;38(3):647-58 PMID: 6091894
  32. Isolation and characterization of bovine and mouse terminal deoxynucleotidyltransferase cDNAs expressible in mammalian cells.
    Nucleic Acids Res. 1986 Jul 25;14(14):5777-92 PMID: 3755527
  33. Molecular components of the B-cell antigen receptor complex of the IgM class.
    Nature. 1990 Feb 22;343(6260):760-2 PMID: 2304550
  34. A novel B-cell lineage-specific transcription factor present at early but not late stages of differentiation.
    Genes Dev. 1990 May;4(5):849-59 PMID: 2116362
  35. Abnormalities of the immune system induced by dysregulated bcl-2 expression in transgenic mice.
    Curr Top Microbiol Immunol. 1990;166:175-81 PMID: 2073796
  36. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene.
    Nature. 1991 Apr 4;350(6317):423-6 PMID: 1901381
  37. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow.
    J Exp Med. 1991 May 1;173(5):1213-25 PMID: 1827140
  38. Expression and function of c-kit in hemopoietic progenitor cells.
    J Exp Med. 1991 Jul 1;174(1):63-71 PMID: 1711568
  39. Anti-immunoglobulin stimulation of B lymphocytes activates src-related protein-tyrosine kinases.
    Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7410-4 PMID: 1714601
  40. The B-cell antigen receptor of the five immunoglobulin classes.
    Nature. 1991 Aug 29;352(6338):777-81 PMID: 1881434
  41. Continued differentiation during B lymphopoiesis requires signals in addition to cell survival.
    Int Immunol. 1997 Oct;9(10):1481-94 PMID: 9352353
  42. Control of B cell development by Ras-mediated activation of Raf.
    EMBO J. 1997 Dec 1;16(23):7019-31 PMID: 9384581
  43. Identification of BSAP (Pax-5) target genes in early B-cell development by loss- and gain-of-function experiments.
    EMBO J. 1998 Apr 15;17(8):2319-33 PMID: 9545244
  44. Loss- and gain-of-function mutations reveal an important role of BSAP (Pax-5) at the start and end of B cell differentiation.
    Semin Immunol. 1998 Apr;10(2):133-42 PMID: 9618759
  45. A critical role of lambda 5 protein in B cell development.
    Cell. 1992 May 29;69(5):823-31 PMID: 1591779
  46. The SCID mouse mutant: definition, characterization, and potential uses.
    Annu Rev Immunol. 1991;9:323-50 PMID: 1910681
  47. The c-kit-encoded tyrosine kinase regulates the proliferation of early pre-B cells.
    Eur J Immunol. 1991 Oct;21(10):2609-12 PMID: 1717287
  48. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship.
    Cell. 1991 Nov 29;67(5):889-99 PMID: 1959134
  49. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement.
    Cell. 1992 Mar 6;68(5):855-67 PMID: 1547487
  50. RAG-1-deficient mice have no mature B and T lymphocytes.
    Cell. 1992 Mar 6;68(5):869-77 PMID: 1547488
  51. Association between B-lymphocyte membrane immunoglobulin and multiple members of the Src family of protein tyrosine kinases.
    Mol Cell Biol. 1992 May;12(5):2315-21 PMID: 1569953
  52. Pax-5 encodes the transcription factor BSAP and is expressed in B lymphocytes, the developing CNS, and adult testis.
    Genes Dev. 1992 Sep;6(9):1589-607 PMID: 1516825
  53. The B cell antigen receptor complex: association of Ig-alpha and Ig-beta with distinct cytoplasmic effectors.
    Science. 1992 Oct 2;258(5079):123-6 PMID: 1439759
  54. Immunoglobulin heavy and light chain genes rearrange independently at early stages of B cell development.
    Cell. 1993 Mar 12;72(5):695-704 PMID: 8453664
  55. Signal transduction by immunoglobulin is mediated through Ig alpha and Ig beta.
    J Exp Med. 1993 Sep 1;178(3):1049-55 PMID: 7688784
  56. The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver.
    J Exp Med. 1993 Sep 1;178(3):951-60 PMID: 8350062
  57. Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice.
    Genes Dev. 1994 May 1;8(9):1030-42 PMID: 7926785
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.188.4.735
Published
1998-08-17
Pages
735-44
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2213350
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.188.4.735 PMC Full Text View journal details
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