The Use of Targeted Mutations in ES Cells to Create Novel Immunodeficient Mouse Models
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.
KeywordsTyrosine Recombination Expense Myeloma Transferase
Unable to display preview. Download preview PDF.
- 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: 6474–6478PubMedCrossRefGoogle Scholar
- 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: 541–543Google Scholar
- Hollingsworth RE Jr, Hensey CE, Lee WH (1993) Retinoblastoma protein arid the cell cycle. Curr Biol 3: 55–62Google Scholar
- Mclntire KR, Rouse AM (1970) Mouse Ig light chains alteration of x/X ratio. Fed Proc 29: 704–708Google Scholar
- Mombaerts P, Iacomini P, Johnson J, Herrup K, Tonegawa S, Papaloannou VE (1992)Google Scholar
- 58.RAG-l-deficient mice have no mature B and T lymphocytes. Cell 68: 869–877Google Scholar
- Nisonoff A, Hopper JE, Spring SB (1975) The antibody molecules. Academic, New YorkGoogle Scholar
- Schatz DG, Oettinger MA, Baltimore D (1990) The V(D) J recombination activating gene, RAG-1. Cell 59: 1035–1048Google Scholar
- 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: 621–624Google Scholar
- 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: 276–290Google Scholar
- 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: 226–233Google Scholar