Abstract
The generation of the immune system is the only known developmental process in mammals that utilizes site-specific genomic recombination mechanisms. B lymphocyte differentiation occurs in fetal liver and adult bone marrow through a well-characterized pathway which includes the ordered assembly of immunoglobulin (Ig) heavy and light chain variable region genes followed by the expression of the assembled Ig chains (Alt et al. 1987, 1992). Likewise, T lymphocyte differentiation follows a similarly ordered program in the thymus, in which developing T cells rearrange and express T cell receptor (TCR)-β and -α chain genes (Davis and Bjorkman 1988; Malissen et al. 1992). Both Ig and TCR variable region genes are assembled by a common enzymatic process referred to as VDJ recombination (Tonegawa 1983; Blackwell and Alt 1989); the VDJ recombinase appears to be expressed only in developing B and T lymphocytes (Alt et al. 1992). The terminal differentiation of mature B cells may involve a different type of site-specific recombinational event referred to as heavy chain class-switch recombination (Blackwell and Alt 1989); this process allows the initially expressed μ constant region gene to be replaced by a different downstream CH gene, while maintaining the same variable region specificity.
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References
Alt FW, Baltimore D (1982) Joining of immunoglobulin heavy chain gene segments: implications from a chromosome with evidence of three D-JH functions. Proc Natl Acad Sci USA 79: 4112–4122
Alt FW, Enea V, Bothwell ALM, Baltimore D (1980) Activity of multiple light chain genes in murine myeloma cells producing a single, functional light chain. Cell 21: 1–12
Alt FW, Yancopoulos GD, Blackwell TK, Wood C, Thomas E, Boss M, Coffman R, Rosenberg N, Tonegawa S, Baltimore D (1984) Ordered rearrangement of immunoglobulin heavy chain variable region segments. EMBO J 3: 1209–1219
Alt FW, Blackwell TK, Yancopoulos GD (1987) Development of primary antibody repertoire. Science 238: 1079–1087
Alt FW, Oltz EM, Young F, Gorman J, Taccioli G, Chen J (1992) VDJ recombination. Immunol Today 13: 306–314
Bernards B, Schackleford GM, Gerber MR, Horowitz JM, Friend SH, Schartl M, Bogenmann E, Rapaport JM, McGee T, Dryja TP, Weinberg RA (1989) Structure and expression of the murine retinoblastoma gene and characterization of its encoded protein. Proc Natl Acad Sci USA 86: 6474–6478
Blackwell TK, Alt FW (1989) Mechanism and developmental program of immunoglobulin gene rearrangement in mammals. Annu Rev Genet 23: 605–636
Blackwell TK, Malynn BA, Pollock RR, Ferrier P, Covey L, Fulop GM, Phillips RA, Yancopoulos GD, Alt FW (1989) Isolation of scid pre-B cells that rearrange kappa light chain genes: formation of normal signal and abnormal coding joins. EMBO J 8: 735–742
Bosma GC, Custer RP, Bosma MJ (1983) A severe combined immunodeficiency mutation in the mouse. Nature 301: 527–530
Charron J, Malynn BA, Fisher P, Stewart V, Jeannotte L, Goff SP, Robertson EJ, Alt FW (1992) Embryonic lethality in mice homozygous for a targeted disruption of the N-myc gene. Genes Dev 6: 2248–2257
Chen J, Alt FW (1993) Gene rearrangement and B–cell development. Curr Opin Immunol 5: 194–200
Chen J, Trounstine M, Alt FW, Young F, Kurahara C, Loring JF, Huszar D (1993a) Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus. Int Immunol 5: 647–656
Chen J, Trounstine M, Kurahara C, Young F, Kuo C-C, Xu Y, Loring JF, Alt FW, Huszar D (1993b) B cell development in mice that lack one or both immunoglobulin k light chain genes. EMBO J 12: 821–830
Chen J, Lansford R, Stewart V, Young F, Alt FW (1993c) RAG-2-deficient blastocyst complementation: an assay of gene function in lymphocyte development. Proc Natl Acad Sci USA 90: 4528–4532
Clark AR, Maandag ER, van Roon M, van der Lug NMT, van der Valk M, Hooper ML, Berns A, te Riele H (1992) Requirement for a functional Rb-1 gene in murine development. Nature 359: 328–330
Coffman RL, Weissman IL (1983) Immunoglobulin gene rearrangement during pre-B cell differentiation. J Mol Cell Immunol 1: 31–38
Coleclough C, Perry RP, Karjalainen K, Weigert M (1981) Aberrant rearrangements contribute significantly to the allelic exclusion of immunoglobulin gene expression. Nature 290: 372–387
Davis MM, Bjorkman PJ (1988) T-cell antigen receptor genes and T-cell recognition. Nature 334: 395–401
DiSanto JP, Bonnefoy JY, Gauchat JF, Fischer A, de Sain Basile G (1993) CD40 ligan mutations in X-linked immunodeficiency with hyper-IgM. Nature 361: 541–543
Ehlich A, Schaal S, Gu H, Kitamura D, Muller W, Rajewsky K (1993) Immunoglobulin heavy and light chain genes rearrange independently at early stages of B cell development. Cell 72: 695–704
Ferrier P, Covey LR, Li SC, Suh H, Malynn BA, Blackwell TK, Morrow MA, Alt FW (1990) Normal recombination substrate VH to DJH rearrangement in pre-B cell lines from seid mice. J Exp Med 171: 1909–1918
Fulop GM, Phillips RA (1990) The seid mutation in mice causes a general defect in DNA repair. Nature 347: 479–482
Fung-Leung W-P, Mak T (1992) Embryonic stem cells and homologous recombination. Curr Opin Immunol 4: 189–194
Hamel PA, Gallie BL, Phillips RA (1992) The retinoblastoma protein and cell cycle regulation. Trends Genet 8: 180–185
Hardy RR, Carmack CE, Shinton SA, Kemp JD, Hayakawa K (1991) Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J Exp Med 173: 1213–1225
Hieter PH, Korsmeyer SJ, Waldmann TA, Leder P (1981) Human immunoglobulin x light-chain genes are deleted or rearranged in X-producing B cells. Nature 290: 368–372
Hollingsworth RE Jr, Hensey CE, Lee WH (1993) Retinoblastoma protein arid the cell cycle. Curr Biol 3: 55–62
Iglesias A, Kopf M, Williams GS, Buhler B, Kohler G (1991) Molecular requirements for the m-induced light chain gene rearrangement in pre-B cells. EMBO J 10: 2147–2156
Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA (1992) Effects of an Rb mutation in the mouse. Nature 359: 295–300
Korthauer U, Graf D, Mages HW, Briere F, Padayachee M, Malcolm S, Ugazio AG, Notarangelo LD, Levinsky RJ, Kroczek RA (1993) Defective expression of T-cell CD40 ligand causes X–linked immunodeficiency with hyper-IgM. Nature 361: 539–541
Lee Ey-HP, Chang C-Y, Hu N, Wang Y-C, Lai C-C, Herrup K, Lee W-H, Bradley A (1992) Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359: 288–294
Lieber MR, Hesse JE, Lewis S, Bosma GC, Rosenberg N, Mizuuchi K, Bosma MJ, Geliert M (1988) The defect in murine severe combined immune deficiency: joining of signal sequences but not coding segments in V(D)J recombination. Cell 55: 7–16
Lutzker S, Rothman P, Pollock R, Coffman R, Alt FW (1988) Mitogen-and IL-4-regulated expression of germ-line Ig y2b transcripts: evidence for directed heavy chain class switching. Cell 53: 177–184
Malissen M, Trucy J, Jouvin-Marche E, Cazenave P-A, Scollay R, Malissen B (1992) Regulation of TCR a and ß gene allelic exclusion during T-cell development. Immunol Today 13: 315–322
Malynn BA, Blackwell, TK, Fulop G, Rathbun GA, Furley AJW, Ferrier P, Heinke LB, Phillips RA, Yancopoulos GD, Alt FW (1988) The seid defect affects the final step of the immunoglobulin V(D)J recombination mechanism. Cell 54: 453–460
Mclntire KR, Rouse AM (1970) Mouse Ig light chains alteration of x/X ratio. Fed Proc 29: 704–708
Mombaerts P, Iacomini P, Johnson J, Herrup K, Tonegawa S, Papaloannou VE (1992)
RAG-l-deficient mice have no mature B and T lymphocytes. Cell 68: 869–877
Nisonoff A, Hopper JE, Spring SB (1975) The antibody molecules. Academic, New York
Nussenzweig M, Shaw AC, Sinn E, Danner DB, Holmes KL, Morse HC, Leder P (1987) Allelic exclusion in transgenic mice that express the membrane form of immunoglobulin \i. Science 236: 816–819
Oettinger MA, Schatz DG, Gorka C, Baltimore D (1990) RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248: 1517–1523
Reichman-Fried M, Hardy RR, Bosma MJ (1990) Development of B–lineage cells in scid mice following the introduction of functionally rearranged immunoglobulin transgenes. Proc Natl Acad Sci USA 87: 2730–2734
Reth MG, Ammiirati P, Jackson S, Alt FW (1985) Regulated progression of a cultured pre-B-cell line to the B-cell stage. Nature 317: 353–355
Rothman P, Li SC, Alt FW (1989) The molecular events in heavy chain class-switching. Semin Immunol 1: 65–77
Schatz DG, Oettinger MA, Baltimore D (1990) The V(D) J recombination activating gene, RAG-1. Cell 59: 1035–1048
Schorle H, HoltschkeT, HunigT, Schimpl A, Horak I (1991) Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352: 621–624
Shinkai Y, Rathbun G, Lam K-P, Oltz EM, Stewart V, Mendelsohn M, Charron J, Datta M, Young F, Stall AM, Alt FW (1992) RAG-2 deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68: 855–867
Shinkai Y, Koyasu S, Nakayama K, Murphy KM, Loh DY, Reinherz EL, Alt FW (1993) Restoration of T cell development in RAG-2-deficient mice by functional TCR transgenes. Science 259: 822–825
Taccioli G, Rathbun G, Oltz G, Stamato T, Jeggo PA, Alt FW (1993) Impairment of V(D)J recombination in double-stranded repair mutants. Science 260: 207–210
Tonegawa S (1983) Somatic generation of antibody diversity. Nature 302: 575–581
Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, Sparkes RS, Kubagawa H, MohandasT, Quan S, Belmont JW, Cooper MD, Conley ME, Witte ON (1993) Deficient expression of a B cell cytoplasmic tyrosine kinase in human x-linked agammaglobulinemia. Cell 72: 276–290
Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, Hammarstrom L, Kinnon C, Levinsky R, Bobrow M, Smith CIE, Bentley DR (1993) The gene involved in x-linked agammaglobulinemia ( XLA) is a member of the src family of protein-tyrosine kinases. Nature 361: 226–233
Zou Y–R, Takeda S, Rajewsky K (1993) Gene targeting in the Igx locus: efficient generation of X expressing B cells independent of gene rearrangements in Igx. EMBO J 12: 811–820
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Alt, F.W., Chen, J. (1994). The Use of Targeted Mutations in ES Cells to Create Novel Immunodeficient Mouse Models. In: Eibl, M.M., Huber, C., Peter, H.H., Wahn, U. (eds) Symposium in Immunology III. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-78438-5_6
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DOI: https://doi.org/10.1007/978-3-642-78438-5_6
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