Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus.

V(D)J recombination assembles antigen receptor variable region genes from component germline variable (V), diversity (D), and joining (J) gene segments. For B cells, such rearrangements lead to the production of immunoglobulin (Ig) proteins composed of heavy and light chains. V(D)J is tightly controlled at the Ig heavy chain locus (IgH) at several different levels, including cell-type specificity, intra- and interlocus ordering, and allelic exclusion. Such controls are mediated at the level of gene segment accessibility to V(D)J recombinase activity. Although much has been learned, many long-standing questions regarding the regulation of IgH locus rearrangements remain to be elucidated. In this review, we summarize advances that have been made in understanding how V(D)J recombination at the IgH locus is controlled and discuss important areas for future investigation.

[1]  A. Carroll,et al.  Light-chain gene expression before heavy-chain gene rearrangement in pre-B cells transformed by Epstein-Barr virus. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[2]  J. Kearney,et al.  Terminal deoxynucleotidyl transferase and repertoire development , 2000, Immunological reviews.

[3]  D. Ramsden,et al.  Mouse VH7183 recombination signal sequences mediate recombination more frequently than those of VHJ558. , 1995, Journal of immunology.

[4]  F. Alt,et al.  Developmentally regulated and strain-specific expression of murine VH gene families , 1988, The Journal of experimental medicine.

[5]  D. Nemazee.  Receptor selection in B and T lymphocytes. , 2000, Annual review of immunology.

[6]  M. Lieber,et al.  The basis for the mechanistic bias for deletional over inversional V(D)J recombination. , 1992, Genes & development.

[7]  K. Rajewsky.  Clonal selection and learning in the antibody system , 1996, Nature.

[8]  M. Reth,et al.  A novel VH to VHDJH joining mechanism in heavy-chain-negative (null) pre-B cells results in heavy-chain production , 1986, Nature.

[9]  J. Kearney,et al.  Organization and expression of immunoglobulin genes in fetal liver hybridomas. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[10]  F. Alt,et al.  Preferential utilization of the most JH-proximal VH gene segments in pre-B-cell lines , 1984, Nature.

[11]  F. Alt,et al.  Transcription-targeted DNA deamination by the AID antibody diversification enzyme , 2003, Nature.

[12]  F. Alt,et al.  Biased expression of JH-proximal VH genes occurs in the newly generated repertoire of neonatal and adult mice , 1990, The Journal of experimental medicine.

[13]  K. Sheehan,et al.  Molecular cloning of the primary IgH repertoire: a quantitative analysis of VH gene usage in adult mice. , 1989, The EMBO journal.

[14]  D. Schatz,et al.  The RAG proteins and V(D)J recombination: complexes, ends, and transposition. , 2000, Annual review of immunology.

[15]  J. Dangl,et al.  Recombination between an expressed immunoglobulin heavy-chain gene and a germline variable gene segment in a Ly 1+ B-cell lymphoma , 1986, Nature.

[16]  David G. Schatz,et al.  Initiation of V(D)J recombination in vitro obeying the 12/23 rule , 1996, Nature.

[17]  S. Desiderio,et al.  Coordination of immunoglobulin DJH transcription and D-to-JH rearrangement by promoter-enhancer approximation , 1991, Molecular and cellular biology.

[18]  M. Krangel,et al.  Regulation of V(D)J recombination: A dominant role for promoter positioning in gene segment accessibility , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[19]  A. Rolink,et al.  Frequencies of multiple IgL chain gene rearrangements in single normal or kappaL chain-deficient B lineage cells. , 1999, Immunity.

[20]  F. Alt,et al.  Developmentally controlled and tissue-specific expression of unrearranged VH gene segments , 1985, Cell.

[21]  D. Trouche,et al.  Chromatin and epigenetics: dynamic organization meets regulated function. , 2003, Molecular cell.

[22]  M. Schlissel,et al.  Changes in Locus-specific V(D)J Recombinase Activity Induced by Immunoglobulin Gene Products during B Cell Development , 1997, The Journal of experimental medicine.

[23]  Vasco M. Barreto,et al.  Frequency and Characterization of Phenotypic Ig Heavy Chain Allelically Included IgM-Expressing B Cells in Mice1 , 2000, The Journal of Immunology.

[24]  R. Perlmutter,et al.  Protein tyrosine kinase p56lck controls allelic exclusion of T-cell receptor β-chain genes , 1993, Nature.

[25]  S. Tonegawa,et al.  Identification of D segments of immunoglobulin heavy-chain genes and their rearrangement in T lymphocytes , 1981, Nature.

[26]  F. Alt,et al.  Class-switch recombination: interplay of transcription, DNA deamination and DNA repair , 2004, Nature Reviews Immunology.

[27]  L. Hood,et al.  Introduced T cell receptor variable region gene segments recombine in pre-B cells: Evidence that B and T cells use a common recombinase , 1986, Cell.

[28]  D. Gray,et al.  Nonequivalent nuclear location of immunoglobulin alleles in B lymphocytes , 2001, Nature Immunology.

[29]  V. Stewart,et al.  Truncated immunoglobulin Dmu causes incomplete developmental progression of RAG-deficient pro-B cells. , 2002, Molecular immunology.

[30]  F. Alt,et al.  Ordered rearrangement of immunoglobulin heavy chain variable region segments. , 1984, The EMBO journal.

[31]  M. Cooper,et al.  Mouse pre-B cells synthesize and secrete μ heavy chains but not light chains , 1980, Cell.

[32]  Steffen Jung,et al.  Epigenetic ontogeny of the Igk locus during B cell development , 2005, Nature Immunology.

[33]  R. Flavell,et al.  Hypersensitive site 7 of the TH2 locus control region is essential for expressing TH2 cytokine genes and for long-range intrachromosomal interactions , 2005, Nature Immunology.

[34]  D. Ramsden,et al.  Initiation of V(D)J recombination in a cell-free system , 1995, Cell.

[35]  L. Cowell,et al.  The "dispensable" portion of RAG2 is necessary for efficient V-to-DJ rearrangement during B and T cell development. , 2002, Immunity.

[36]  V. Stewart,et al.  RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement , 1992, Cell.

[37]  P. Fraser,et al.  Antisense intergenic transcription in V(D)J recombination , 2004, Nature Immunology.

[38]  K. G. Nickerson,et al.  VH gene usage in humans: biased usage of the VH6 gene in immature B lymphoid cells , 1991, European journal of immunology.

[39]  David Jung,et al.  Unraveling V(D)J Recombination Insights into Gene Regulation , 2004, Cell.

[40]  Sheryl K Elkin,et al.  A PHD Finger Motif in the C Terminus of RAG2 Modulates Recombination Activity*[boxs] , 2005, Journal of Biological Chemistry.

[41]  Heikyung Suh,et al.  Chromosomal position of rearranging gene segments influences allelic exclusion in transgenic mice. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[42]  R. Brinster,et al.  Allelic exclusion and control of endogenous immunoglobulin gene rearrangement in κ transgenic mice , 1984, Nature.

[43]  T. Honjo,et al.  Class Switch Recombination and Hypermutation Require Activation-Induced Cytidine Deaminase (AID), a Potential RNA Editing Enzyme , 2000, Cell.

[44]  F. Alt,et al.  Allelic Exclusion of the T Cell Receptor β Locus Requires the Sh2 Domain–Containing Leukocyte Protein (Slp)-76 Adaptor Protein , 1999, The Journal of experimental medicine.

[45]  F. Melchers,et al.  λ5, a new light-chain-related locus selectively expressed in pre-B lymphocytes , 1986, Nature.

[46]  Sheryl K Elkin,et al.  Deletion of the RAG2 C terminus leads to impaired lymphoid development in mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[47]  T. Imanishi‐Kari,et al.  Endogenous immunoglobulin expression in mu transgenic mice. , 1991, International immunology.

[48]  S. Tonegawa,et al.  Somatic generation of antibody diversity. , 1976, Nature.

[49]  F. Burnet.  A modification of jerne's theory of antibody production using the concept of clonal selection , 1976, CA: a cancer journal for clinicians.

[50]  L. Herzenberg,et al.  A high frequency of hybridomas from M54 mu heavy chain transgenic mice initially co-express transgenic and rearranged endogenous mu genes. , 1993, International immunology.

[51]  G. Wu,et al.  Inversions produced during V(D)J rearrangement at IgH, the immunoglobulin heavy-chain locus , 1995, Molecular and cellular biology.

[52]  F. Alt,et al.  A class switch control region at the 3′ end of the immunoglobulin heavy chain locus , 1994, Cell.

[53]  L. Hood,et al.  Separate elements control DJ and VDJ rearrangement in a transgenic recombination substrate. , 1990, The EMBO journal.

[54]  K. Rajewsky,et al.  Targeted disruption of µ chain membrane exon causes loss of heavy-chain allelic exclusion , 1992, Nature.

[55]  K. Sheehan,et al.  The utilization of individual VH exons in the primary repertoire of adult BALB/c mice. , 1993, Journal of immunology.

[56]  A. Feeney,et al.  E2A and EBF act in synergy with the V(D)J recombinase to generate a diverse immunoglobulin repertoire in nonlymphoid cells. , 2000, Molecular cell.

[57]  T. Winkler,et al.  In-vitro analyses of mechanisms of B-cell development. , 1995, Seminars in immunology.

[58]  K. Rajewsky,et al.  In Vivo Ablation of Surface Immunoglobulin on Mature B Cells by Inducible Gene Targeting Results in Rapid Cell Death , 1997, Cell.

[59]  Roy Riblet,et al.  Visualization of looping involving the immunoglobulin heavy-chain locus in developing B cells. , 2005, Genes & development.

[60]  M. Busslinger,et al.  Locus 'decontraction' and centromeric recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene , 2005, Nature Immunology.

[61]  A. Chess,et al.  Asynchronous replication and allelic exclusion in the immune system , 2001, Nature.

[62]  F. Alt,et al.  Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus. , 1993, International immunology.

[63]  F. Alt,et al.  Regulation of immunoglobulin light chain isotype expression. , 1998, Advances in immunology.

[64]  F. Alt,et al.  The Mechanism and Regulation of Chromosomal V(D)J Recombination , 2002, Cell.

[65]  F. Melchers,et al.  A second gene, VpreB in the lambda 5 locus of the mouse, which appears to be selectively expressed in pre‐B lymphocytes. , 1987, The EMBO journal.

[66]  D. Schatz,et al.  B cell–specific loss of histone 3 lysine 9 methylation in the VH locus depends on Pax5 , 2004, Nature Immunology.

[67]  K. Rajewsky,et al.  A Prematurely Expressed Igκ Transgene, but Not a VκJκ Gene Segment Targeted into the Igκ Locus, Can Rescue B Cell Development in λ5-Deficient Mice , 1996 .

[68]  J. Kearney,et al.  Development and function of the early B cell repertoire. , 1992, International reviews of immunology.

[69]  E. L. Prak,et al.  Immunoglobulin heavy chain gene replacement: a mechanism of receptor editing. , 1995, Immunity.

[70]  S. Desiderio,et al.  The cell cycle and V(D)J recombination. , 1996, Current topics in microbiology and immunology.

[71]  J. Cebra,et al.  RABBIT LYMPHOID CELLS DIFFERENTIATED WITH RESPECT TO α-, γ-, AND µ- HEAVY POLYPEPTIDE CHAINS AND TO ALLOTYPIC MARKERS AA1 AND AA2 , 1966, The Journal of experimental medicine.

[72]  F. Alt,et al.  Regulation of the assembly and expression of variable-region genes. , 1986, Annual review of immunology.

[73]  Y. Shinkai,et al.  Targeted inhibition of V(D)J recombination by a histone methyltransferase , 2004, Nature Immunology.

[74]  F. Sablitzky,et al.  V(D)J recombination in B cells is impaired but not blocked by targeted deletion of the immunoglobulin heavy chain intron enhancer. , 1993, The EMBO journal.

[75]  L. Hood,et al.  An immunoglobulin heavy chain variable region gene is generated from three segments of DNA: VH, D and JH , 1980, Cell.

[76]  M. Reth,et al.  Crosslinking of the cell surface immunoglobulin (mu-surrogate light chains complex) on pre-B cells induces activation of V gene rearrangements at the immunoglobulin kappa locus. , 1992, International immunology.

[77]  S. Tonegawa,et al.  A tissue-specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy chain gene , 1983, Cell.

[78]  F. Alt,et al.  Elucidation of IgH intronic enhancer functions via germ-line deletion. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[79]  Sean D. Taverna,et al.  Antigen receptor loci poised for V(D)J rearrangement are broadly associated with BRG1 and flanked by peaks of histone H3 dimethylated at lysine 4 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[80]  R. Perry,et al.  Aberrant rearrangements contribute significantly to the allelic exclusion of immunoglobulin gene expression , 1981, Nature.

[81]  S. Ryser,et al.  In transgenic mice the introduced functional T cell receptor beta gene prevents expression of endogenous beta genes. , 1988, Cell.

[82]  J. Rogers,et al.  Two mRNAs can be produced from a single immunoglobulin μ gene by alternative RNA processing pathways , 1980, Cell.

[83]  J. Yagüe,et al.  Rearrangement of T-cell receptor beta-chain genes during T-cell development. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[84]  F. Alt,et al.  Chromatin dynamics and locus accessibility in the immune system , 2003, Nature Immunology.

[85]  F. Alt,et al.  Activation of V kappa gene rearrangement in pre‐B cells follows the expression of membrane‐bound immunoglobulin heavy chains. , 1987, The EMBO journal.

[86]  D. Baltimore,et al.  Formation of disulphide-linked µ2ω2 tetramers in pre-B cells by the 18K ω-immunoglobulin light chain , 1987, Nature.

[87]  C. Hasemann,et al.  Novel rearrangements at the immunoglobulin D locus. Inversions and fusions add to IgH somatic diversity , 1989, The Journal of experimental medicine.

[88]  M. Busslinger.  Transcriptional control of early B cell development. , 2004, Annual review of immunology.

[89]  K. Rajewsky,et al.  B cell development regulated by gene rearrangement: Arrest of maturation by membrane-bound Dμ protein and selection of DH element reading frames , 1991, Cell.

[90]  G. Köhler,et al.  A second promoter and enhancer element within the immunoglobulin heavy chain locus , 1994, European journal of immunology.

[91]  D. Schatz,et al.  Pax5 is required for recombination of transcribed, acetylated, 5' IgH V gene segments. , 2003, Genes & development.

[92]  F. Alt,et al.  Extrachromosomal recombination substrates recapitulate beyond 12/23 restricted VDJ recombination in nonlymphoid cells. , 2003, Immunity.

[93]  A. Riddell,et al.  Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor , 1998, Nature.

[94]  B. Sleckman,et al.  Allelic exclusion at the TCRβ locus , 2002 .

[95]  P. Brodeur,et al.  Cutting Edge: Stat5 Mediates the IL-7-Induced Accessibility of a Representative D-Distal VH Gene1 , 2005, The Journal of Immunology.

[96]  M. Nussenzweig,et al.  Control of immunoglobulin gene rearrangements in developing B cells. , 1997, Current opinion in immunology.

[97]  F. Alt,et al.  The Lingering Enigma of the Allelic Exclusion Mechanism , 2004, Cell.

[98]  I. Weissman,et al.  Immunoglobulin gene rearrangement during pre-B cell differentiation. , 1983, The Journal of molecular and cellular immunology : JMCI.

[99]  L. Hood,et al.  Developmentally controlled expression of immunoglobulin VH genes. , 1985, Science.

[100]  R. Hardy,et al.  B cell development pathways. , 2001, Annual review of immunology.

[101]  S. Batalov,et al.  Antisense Transcription in the Mammalian Transcriptome , 2005, Science.

[102]  A. Shaffer,et al.  Cell Type–Specific Chromatin Structure Determines the Targeting of V(D)J Recombinase Activity In Vitro , 1996, Cell.

[103]  D. Mason,et al.  The structure of the μ/pseudo light chain complex on human pre‐B cells is consistent with a function in signal transduction , 1993, European journal of immunology.

[104]  M. Nussenzweig,et al.  V(D)J Recombination: Modulation of RAG1 and RAG2 Cleavage Activity on 12/23 Substrates by Whole Cell Extract and DNA-bending Proteins , 1997, The Journal of experimental medicine.

[105]  F. Alt,et al.  Impaired V(D)J Recombination and Lymphocyte Development in Core RAG1-expressing Mice , 2003, The Journal of experimental medicine.

[106]  F. Alt,et al.  Joining of immunoglobulin heavy chain gene segments: implications from a chromosome with evidence of three D-JH fusions. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[107]  M. Schlissel,et al.  Pax5 Activates Immunoglobulin Heavy Chain V to DJ Rearrangement in Transgenic Thymocytes , 2004, The Journal of experimental medicine.

[108]  M. Reth,et al.  B cell signaling and tumorigenesis. , 2005, Annual review of immunology.

[109]  E. L. Prak,et al.  Editing disease-associated autoantibodies. , 1997, Immunity.

[110]  F. Alt,et al.  Regulation of Genome Rearrangement Events during Lymphocyte Differentiation , 1986, Immunological reviews.

[111]  A. Rolink,et al.  Changes in the V(H) gene repertoire of developing precursor B lymphocytes in mouse bone marrow mediated by the pre-B cell receptor. , 1997, Immunity.

[112]  L. Hood,et al.  Amino acid sequence of homogeneous antibodies to dextran and DNA rearrangments in heavy chain V-region gene segments , 1980, Nature.

[113]  R. Perlmutter,et al.  Protein tyrosine kinase p56lck controls allelic exclusion of T-cell receptor beta-chain genes. , 1993, Nature.

[114]  David Baltimore,et al.  Organization and reorganization of immunoglobulin genes in A-MuLV-transformed cells: Rearrangement of heavy but not light chain genes , 1981, Cell.

[115]  H. Igarashi,et al.  Cross-linking of B cell receptor-related MB-1 molecule induces protein tyrosine phosphorylation in early B lineage cells. , 1993, Journal of immunology.

[116]  H. Erdjument-Bromage,et al.  A direct interaction between the RAG2 C terminus and the core histones is required for efficient V(D)J recombination. , 2005, Immunity.

[117]  M. Krangel.  Gene segment selection in V(D)J recombination: accessibility and beyond , 2003, Nature Immunology.

[118]  D. Nemazee,et al.  Revising B Cell Receptors , 2000, The Journal of experimental medicine.

[119]  V. Stewart,et al.  Mutations of the intronic IgH enhancer and its flanking sequences differentially affect accessibility of the JH locus. , 1993, The EMBO journal.

[120]  Susumu Tonegawa,et al.  RAG-1-deficient mice have no mature B and T lymphocytes , 1992, Cell.

[121]  R. Sen,et al.  Regulation of immunoglobulin heavy‐chain gene rearrangements , 2004, Immunological reviews.

[122]  A. Rolink,et al.  Precursor B cells showing H chain allelic inclusion display allelic exclusion at the level of pre-B cell receptor surface expression. , 1998, Immunity.

[123]  C. Ware,et al.  Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice , 1994, The Journal of experimental medicine.

[124]  F. Alt,et al.  Dramatically Increased Rearrangement and Peripheral Representation of Vβ14 Driven by the 3′Dβ1 Recombination Signal Sequence , 2003 .

[125]  F. Alt,et al.  Assembly of Productive T Cell Receptor δ Variable Region Genes Exhibits Allelic Inclusion , 1998, The Journal of experimental medicine.

[126]  E. Sasso,et al.  Chromosomal organization of the heavy chain variable region gene segments comprising the human fetal antibody repertoire. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[127]  S. Tonegawa,et al.  Immunoglobulin gene rearrangement in immature B cells. , 1980, Science.

[128]  Christina A. Cuomo,et al.  Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps , 1995, Cell.

[129]  P. Lanerolle,et al.  Actin and myosin I in the nucleus: what next? , 2005, Nature Structural &Molecular Biology.

[130]  F. Alt,et al.  Regulated progression of a cultured pre-B-cell line to the B-cell stage , 1985, Nature.

[131]  M. Schlissel,et al.  Variegated Transcriptional Activation of the Immunoglobulin κ Locus in Pre-B Cells Contributes to the Allelic Exclusion of Light-Chain Expression , 2004, Cell.

[132]  F. Alt,et al.  Activity of multiple light chain genes in murine myeloma cells producing a single, functional light chain , 1980, Cell.

[133]  A. Feeney,et al.  Unequal VH Gene Rearrangement Frequency Within the Large VH7183 Gene Family Is Not Due to Recombination Signal Sequence Variation, and Mapping of the Genes Shows a Bias of Rearrangement Based on Chromosomal Location1 , 2001, The Journal of Immunology.

[134]  J. Banerji,et al.  A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes , 1983, Cell.

[135]  F. Alt,et al.  Position-dependent inhibition of class-switch recombination by PGK-neor cassettes inserted into the immunoglobulin heavy chain constant region locus. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[136]  M. Reth.  Antigen receptors on B lymphocytes. , 1992, Annual review of immunology.

[137]  Benvenuto Pernis,et al.  CELLULAR LOCALIZATION OF IMMUNOGLOBULINS WITH DIFFERENT ALLOTYPIC SPECIFICITIES IN RABBIT LYMPHOID TISSUES , 1965, The Journal of experimental medicine.

[138]  P. Leder,et al.  Allelic exclusion in transgenic mice that express the membrane form of immunoglobulin mu. , 1987, Science.

[139]  F. Alt,et al.  Recombination signal sequences restrict chromosomal V(D)J recombination beyond the 12/23 rule , 2000, Nature.

[140]  M. Sadofsky.  Recombination‐activating gene proteins: more regulation, please , 2004, Immunological reviews.

[141]  F. Alt,et al.  Immature thymocytes employ distinct signaling pathways for allelic exclusion versus differentiation and expansion. , 1999, Immunity.

[142]  B. Chait,et al.  Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement , 2003, Nature Immunology.

[143]  J. Pelkonen,et al.  Deletion of the DQ52 Element Within the Ig Heavy Chain Locus Leads to a Selective Reduction in VDJ Recombination and Altered D Gene Usage , 2001, The Journal of Immunology.

[144]  R. Riblet.  CHAPTER 2 – Immunoglobulin Heavy Chain Genes of Mouse , 2004 .

[145]  D. Baltimore,et al.  A transgenic immunoglobulin Mu gene prevents rearrangement of endogenous genes , 1985, Cell.

[146]  M. Cooper,et al.  The molecular basis and biological significance of VH replacement , 2004, Immunological reviews.

[147]  F. Alt,et al.  The role of the non‐homologous end‐joining pathway in lymphocyte development , 2004, Immunological reviews.

[148]  R. Sen,et al.  Transient IL-7/IL-7R signaling provides a mechanism for feedback inhibition of immunoglobulin heavy chain gene rearrangements. , 2003, Immunity.

[149]  Tetsuya Nakamura,et al.  Unexpected requirement for ZAP-70 in pre-B cell development and allelic exclusion. , 2003, Immunity.

[150]  A. Chess,et al.  Kappa chain monoallelic demethylation and the establishment of allelic exclusion. , 1998, Genes & development.

[151]  S. L. Bridges,et al.  Contribution of Vh gene replacement to the primary B cell repertoire. , 2003, Immunity.

[152]  J. Ihle,et al.  Regulation of interleukin 7–dependent immunoglobulin heavy-chain variable gene rearrangements by transcription factor STAT5 , 2005, Nature Immunology.

[153]  M. Walter,et al.  Physical linkage of a human immunoglobulin heavy chain variable region gene segment to diversity and joining region elements. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[154]  S. Ryser,et al.  In transgenic mice the introduced functional T cell receptor β gene prevents expression of endogenous β genes , 1988, Cell.

[155]  Mark M. Davis,et al.  T-cell antigen receptor genes and T-cell recognition , 1988, Nature.

[156]  B. Haines,et al.  Accessibility changes across the mouse Igh‐V locus during B cell development , 1998, European journal of immunology.

[157]  Yung Chang,et al.  Extended Duration of DH–JH Rearrangement in Immunoglobulin Heavy Chain Transgenic Mice: Implications for Regulation of Allelic Exclusion , 1999, The Journal of experimental medicine.

[158]  I. Mårtensson,et al.  The pre-B cell receptor and its role in proliferation and Ig heavy chain allelic exclusion. , 2002, Seminars in immunology.

[159]  David Baltimore,et al.  Synthesis of secreted and membrane-bound immunoglobulin mu heavy chains is directed by mRNAs that differ at their 3′ ends , 1980, Cell.

[160]  F. Alt,et al.  Novel immunoglobulin heavy chains are produced from DJH gene segment rearrangements in lymphoid cells , 1984, Nature.

[161]  K. Rajewsky,et al.  Immunoglobulin heavy and light chain genes rearrange independently at early stages of B cell development , 1993, Cell.

[162]  H. Jäck,et al.  Surrogate light chain-dependent selection of Ig heavy chain V regions. , 1995, Journal of immunology.

[163]  Roy Riblet,et al.  Subnuclear Compartmentalization of Immunoglobulin Loci During Lymphocyte Development , 2002, Science.

[164]  D. Baltimore,et al.  Virus-transformed pre-B cells show ordered activation but not inactivation of immunoglobulin gene rearrangement and transcription , 1991, The Journal of experimental medicine.

[165]  T. Winkler,et al.  Regulation of recombination activating gene expression during lymphocyte development. , 1996, Current topics in microbiology and immunology.

[166]  F. Alt,et al.  VH to VHDJH rearrangement is mediated by the internal VH heptamer. , 1990, International immunology.

[167]  R. Sen,et al.  Stepwise activation of the immunoglobulin μ heavy chain gene locus , 2001, The EMBO journal.

[168]  C. Coleclough.  Chance, necessity and antibody gene dynamics , 1983, Nature.

[169]  Roland Eils,et al.  A contractile nuclear actin network drives chromosome congression in oocytes , 2005, Nature.

[170]  M. Busslinger,et al.  Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. , 2004, Genes & development.

[171]  S. Rusconi,et al.  Transmission and expression of a specific pair of rearranged immunoglobulin mu and kappa genes in a transgenic mouse line. , 1985, Nature.

[172]  M. Schlissel,et al.  Ig heavy chain protein controls B cell development by regulating germ-line transcription and retargeting V(D)J recombination. , 1994, Journal of immunology.

[173]  F. Alt,et al.  Recombination and transcription of the endogenous Ig heavy chain locus is effected by the Ig heavy chain intronic enhancer core region in the absence of the matrix attachment regions. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[174]  M. Lieber,et al.  The role of recombination signal sequences in the preferential joining by deletion in DH-JH recombination and in the ordered rearrangement of the IgH locus. , 1997, International immunology.