Generation of α1,3Galactosyltransferase Deficient Mice

  • Aron D. Thall
Part of the Subcellular Biochemistry book series (SCBI, volume 32)


All mammals, with the exception of apes, Old World monkeys, and humans possess a functional α1,3GT gene (Galili et al., 1990). Microsomal preparations from tissues of mammalian species as divergent as pigs, cows, New World monkey and mice all contain α1,3GT activity, capable of transferring Gal onto terminal N-acetyllactosamine containing glycolipids and glycoproteins (Thall et al., 1991a). As no other mammalian α 1,3GT genes have been cloned, it was assumed but not proven that this α 1,3GT gene is responsible for the synthesis of all α-gal epitopes in mammals other than apes, Old World Monkeys and humans. This enzymatic activity is distinct from the blood group B α1,3GT, which requires a terminal α 1,2-Fuc linked to N-acetyllactosamine as the acceptor structure and is active only in primates (Elices et al., 1986).


Zona Pellucida World Monkey Apice Group Coat Color Chimerism Agouti Coat Color 
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  1. Barondes, S.H., Cooper, D.N., Gitt, M.A., and Leffler, H., 1994.Galectins. Structure and function of a large family of animallectins. J. Biol. Chem.. 269: 20807–20810.PubMedGoogle Scholar
  2. Betz, U.A., Vosshenrich, C.A., Rajewsky, K., and Muller.W., 1996. Bypass of lethality with mosaic mice generated by Cre-loxP-mediated recombination. Curro Biol., 6: 1307–1316.CrossRefGoogle Scholar
  3. Bleil, J.D. and Wassarman, P.M., 1988. Galactose at the nonreducing terminus ofO-linked oligosaccharides of mouse egg zona pellucida glycoprotein ZP3 is essential for the glycoprotein’s sperm receptor activity. Proc. Natl. Acad. Sci., 85: 6778–6782.PubMedCrossRefGoogle Scholar
  4. Buchholz, F., Ringrose, L., Angrand, P.O., Rossi, F., and Stewart, A.F., 1996. Different thennostabilities ofFLP and Cre recombinases: implications for applied site-specific recombination, Nucleic Acids Res., 24: 4256–4262.PubMedCrossRefGoogle Scholar
  5. Colson, Y.L., Wren, S.M., Schuchert, M.J., Patrene, K.D., Johnson, P.C., Boggs, S.S., and Ildstad, S.T., 1995. A nonlethal conditioning approach to achieve durable multilineage mixed chimerism and tolerance across major. minor. and hematopoietic histocompatibility barriers. J. Immunol., 155: 4179–4188.PubMedGoogle Scholar
  6. Cooper, O.K., Good, A.H., Koren, E., Oriol, R., Malcolm, AJ., Ippolito, R.M., Neethling, F.A., Yeo Y., Romano, E., and Zuhdi, N., 1993. Identification of alpha-galactosyl and other carbohydrate epitopes that are bound by human anti-pig antibodies: relevance to discordant xenografting in man. Transpl. lmmunol., 1: 198–205.CrossRefGoogle Scholar
  7. Cooper, O.K. and Thall, A.D., 1997. Xenoantigens and xenoantibodies: their modification, World J. Surg., 21: 901–906.PubMedCrossRefGoogle Scholar
  8. Cummings, R.D. and Mattox, S.A., 1988. Retinoic acid-induced differentiation of the mouse teratocarcinoma cell line F9 is accompanied by an increase in the activity of UDP-galactose: beta-D-galactosyl-alpha 1,3-galactosyltransferase. J. Biol. Chem., 263: 511–519.PubMedGoogle Scholar
  9. Doetschman, T.e., Eistetter, H., Katz, M., Schmidt, W., and Kemler, R. J.,1985,The in vitro development of blastocyst-derived embryonic stem cel1lines: formation of visceral yolk sac, blood islands and myocardium, Embryol. Exp. Morph., 87: 27–45.Google Scholar
  10. Elices, MJ., Blake, D.A., and Goldstein, I.J., 1986. Purification and characterization of a UDPGal: beta-D-Gal(1.4)-D-GIcNAca(1.3)-galactosyltransferase from Ehrlich ascites tumor cells, J. Biol. Chem., 261: 6064–6072.PubMedGoogle Scholar
  11. Etienne-Decerf, J., Malaise, M., Mahieu, P., and Winand, R., 1987. Elevated anti-alpha-galactosyl antibody titres. A marker of progression in autoimmune thyroid disorders and in endocrine ophthalmopathy? Acta Endocrinol. (Copenh)., 115: 67–74.Google Scholar
  12. Galili, U., Mandrell, R.E., Harndeh, R.M., Shohet, S.B. and Griffis, IM., 1988b. Interaction between human natural anti-alpha-galactosyl immunoglobulin G and bacteria of the human flora, Infect. Immun., 57: 1730–1737.Google Scholar
  13. Galili, U., Rachrnilewitz, E.A., Peleg, A. and Flechner, I., 1984,Aunique natural human IgG antibody with anti-alpha-galactosyl specificity. J. Exp. Med., 160: 1519–1531.PubMedCrossRefGoogle Scholar
  14. Galili, U. and Swanson, K., 1991, Gene sequences suggest inactivation of α-l,3-galactosyltransferase in catarrhines after the divergence of apes from monkeys, Proc. Natl. Acad. Sci., 88: 7401–7404.PubMedCrossRefGoogle Scholar
  15. Galili, U., Thall, A., and Macher, B.A., 1990, Evolution of the Galαl®3Galβl®4GlcNAc epitope in mammals, Trends in Glycoscience and Glycolechnology, 2: 308–318.Google Scholar
  16. Galili, U., Shohet, S.B., Kobrin, E., Stults, C.L. and Macher, B.A., 1988a, Man, apes, and Old World monkeys differ from other mammals in the expression of alpha-galactosyl epitopes on nucleated cells,J. Biol. Chem., 263: 17755–17762.PubMedGoogle Scholar
  17. Grimstad, I.A. and Bosnes, V., 1987, Cell-surface laminin-like molecules and alpha-D-galactopyranosyl end-groups of cloned strongly and weakly metastatic murine fibrosarcoma cells. Int. J. Cancer, 40: 505–510.PubMedCrossRefGoogle Scholar
  18. Grimstad, I.A., Varani J., and McCoy, J.P. Jr, 1984, Contribution of α-D-galactopyranosyl end groups to attachment of highly and low metastatic murine fibrosarcoma cells to various substrates, Exp. Cell Res., 155: 345–358.PubMedCrossRefGoogle Scholar
  19. Henion, T.R., Macher, B.A., Anaraki, F., and Galili U., 1994, Defining the minimal size of catalytically active primate alpha l,3galactosyltransferase: structure-function studies on the recombinant truncated enzyme, Glycobiology, 4: 193–201.PubMedCrossRefGoogle Scholar
  20. Inverardi L, Clissi B, Stolzer AL, Bender JR, Sandrin MS, and Pardi R., 1997, Human natural killer lymphocytes directly recognize evolutionarily conserved oligosaccharide ligands expressed by xenogeneic tissues, Transplantation, 63: 1318–1330.PubMedCrossRefGoogle Scholar
  21. Johnston, D.S., Wright, W.W., Shaper, J.H., Hokke, C.H., Van den Eijnden, D.H., and Joziasse, D.H., 1998, Murine sperm-zona binding, a fucosyl residue is required for a high affinity sperm-binding ligand. A second site on sperm binds a nonfucosylated, betα-galactosyl-capped oligosaccharide, J. Biol. Chem., 273: 1888–1895.PubMedCrossRefGoogle Scholar
  22. Joziasse, D.H., Shaper, J.H., Jabs, E.W., and Shaper, N.L, 1991, Characterization of an α 1,3-galactosyltransferase homologue on human chromosome 12 that is organized as a processed psuedogene, J. Biol. Chem., 266: 6991–6998.PubMedGoogle Scholar
  23. Joziasse, D.H., Shaper, N.L., Shaper, J.H., and Kozak, C.A., 1991, Gene for murine α 1,3-galactosyltrasferase is located in the centromeric region of chromosome 2. Soma.t Cell Mol.Genet, 17: 201–205.CrossRefGoogle Scholar
  24. Joziasse, D.H., Shaper, N.L., Kim, D., Van den Eijnden, D.H., and Shaper, J.H., 1992, Murine α 1,3-galactosyltransferase. A single gene locus specifies four isoforms of the enzyme by alternative splicing, J. Biol. Chem., 267: 5534–5541.PubMedGoogle Scholar
  25. Kim, M., Rao, M.V., Tweardy, D.J., Prakash, M., Galili, U., and Gorelik, E., 1993, Lectin-induced apoptosis of tumour cells. Glycobiology, 3:447–453.PubMedCrossRefGoogle Scholar
  26. Knibbs, R.N., Agrwal, N., Wang, J.L., and Goldstein, I.J., 1993, Carbohydrate-binding protein 35. II. Analysis of the interaction of the recombinant polypeptide with saccharides, J. Biol. Chem., 268: 14940–14947.PubMedGoogle Scholar
  27. Larsen R.D., Riverα-Marrero C.A., Ernst, L.K., Cummings R.D., and Lowe, J.B., 1990, Frameshift and nonsense mutations in a human genomic sequence homologous to a murine UDP-Gal:β-D-Gal(l,4)-D-GlcNac α(l,3)-galactosyltransferase cDNA, J. Biol. Chem., 265:7055–7061.PubMedGoogle Scholar
  28. Larsen, R.D., Rajan, V.P., Ruff, M.M., Kukowskα-Latallo, J., Cummings, R.D., and Lowe, J.B., 1989 Isolation of a cDNA encoding a murine UDP-galactose:β-D-galactosyl-l,4-N-acetyl-D-glucosaminide α-l,3-galactosyltransferase: Expression cloning by gene transfer, Proc. Natl. Acad. Sci. USA, 86: 8227–8231.PubMedCrossRefGoogle Scholar
  29. Litscher, E. S., Juntunen, K., Seppo, A., Penttila, L., Niemela R., Renkonen, O., and Wassarman, P. M., 1995, Oligosaccharide constructs with defined structures that inhibit binding of mouse sperm to unfertilized eggs in vitro, Biochemistry, 34: 4662–4669.PubMedCrossRefGoogle Scholar
  30. Maddox, D.E., Shibata, S., Goldstein, I.J., 1982, Stimulated macrophages express a new glycoprotein receptor reactive with Griffonia simplicifolia 1-B4 isolectin, Proc. Natl. Acad. Sci. USA, 79:166–170.PubMedCrossRefGoogle Scholar
  31. Marth, J.D., 1996. Recent advances in gene mutagenesis by site-directed recombination, J. Clin. Invest., 97: 1999–2002.PubMedCrossRefGoogle Scholar
  32. McBurney, M.W., Sutherland, L.C., Adra, B., Leclair, B., Rudnicki, M.A., and Jardine, K.X., 1991. The mouse Pgk-1 gene promoter contains an upstream activator sequence. Nucleic Acids Res., 19:5755–5761.PubMedCrossRefGoogle Scholar
  33. McCoy, J.P. Jr., Varani, J., and Goldstein, I.J., 1983. Enzyme-linked lectin assay (ELLA): useof alkaline phosphatase-conjugated Griffonia simplicifolia B4 isolectin for the detection of alpha-D-galactopyranosyl end groups. Anal. Biochem., 130: 437–444.PubMedCrossRefGoogle Scholar
  34. McEver, R.P., Moore, K.L., and Cummings, R.D., 1995. Leukocyte trafficking mediated by selectin-carbohydrate interactions. J. Biol. Chem., 270: 11025–11028.PubMedCrossRefGoogle Scholar
  35. Mc Whir, J., Schnieke, A.E., Ansell, R., Wallace, H., Colman, A., Scott, A.R., and Kind, A.J., 1996. Selective ablation of differentiated cells permits isolation of embryonic stem cell lines from murine embryos with a non-permissive genetic background. Nat. Genet., 14: 223–226.CrossRefGoogle Scholar
  36. Miller, D.J. Macek, M.B., and Shur, B.D.,1992. Complementarity between sperm surface betα-1.4-galactosyltransferase and egg-coat ZP3 mediates sperm-egg binding. Nature, 357: 589–593.PubMedCrossRefGoogle Scholar
  37. Moody, D.B., Reinhold, B.B., Guy, M.R., Beckman, E.M., Frederique, D.E., Furlong, S.T., Ye, S., Reinhold, V.N., Sieling, P.A., Modlin, R.L., Besra, G.S., and Porcelli, S.A., 1997, Structural requirements for glycolipid antigen recognition by CD 1 b-restricted T cells. Science, 278: 283–286.PubMedCrossRefGoogle Scholar
  38. Niemela, R., Penttila, L., Seppo, A., Helin, J., Leppanen, A., Rabina, J., Uusitalo, L., Maaheimo, H., Taskinen, J., Costello C.E., and Renkonen, O., 1995. Enzyme-assisted synthesis of a bivalent high-affinity dodecasaccharide inhibitor of mouse gamete adhesion. The length of the chains carrying distal α 1,3-bonded galactose residues is critical. FEBS Leu. 367: 67–72.CrossRefGoogle Scholar
  39. Ogiso, M., Hidehiko, S.,and Hoshi, M., 1998. Localization of Lew is sialyl-Lewis and α-galactosyl epitopes on glycosphingolipids in lens tissues. Glycobiologv. 8: 95–105.CrossRefGoogle Scholar
  40. Platt, J.L., 1994. A perspective on xenograft rejection and accommodation. Immunol. Rev., 141: 127–149.PubMedCrossRefGoogle Scholar
  41. Russell, P.S., Chase, C.M., and Colvin, R.B., 1997. Alloantibody-and T cell-mediated immunity in the pathogenesis of transplant arteriosclerosis: lack of progression to sclerotic lesions in B cell-deficient mice. Transplantation. 64: 1531–1536.PubMedCrossRefGoogle Scholar
  42. Sandrin, M.S., Vaughan, H.A., Dabkowski, P.L., and McKenzie, I.F.C., 1993. Anti-pig IgM antibodies in human serum react predominantly with Gal(α1–3)Gal epitopes, Proc. Natnl Acad. Sci., 90: 11391–11395.CrossRefGoogle Scholar
  43. Sandrin, M.S., Vaughan, H.A., Xing, P.-X., and McKenzie, I.F.C., 1997. Natural anti-Galα 1.3Gal antibodies react with human mucin peptides. Glycoconj. J., 14: 97–105.PubMedCrossRefGoogle Scholar
  44. Simon, P.M., Neethling, F.A., Taniguchi, S., Goode, P.L., Zopf, D., Hancock, W.W., and Cooper, D.K., 1998. Intravenous infusion of Gal alpha 1-3Gal oligosaccharides in baboons delays hyperacute rejection of porcine heart xenografts. Transplantation. 65: 346–353.PubMedCrossRefGoogle Scholar
  45. Smith, D.F., Larsen, R.D., Mattox, S., Lowe, J.B., and Cummings, R.D., 1990, Transfer and expression of a murine UDP-Gal:β-D-Gal-α-1,3-galactosyltransferase gene in transfected Chinese hamster ovary cells. J. Biol. Chem., 265: 6225–6234.PubMedGoogle Scholar
  46. Strahan, K.M., Gu, F., Preece, A.F., Gustavsson, I., Andersson, L., and Gustafsson, K., 1995, cDNA sequence and chromosome localization of pig alpha 1.3 cDNA sequence and chromosome localization of pig alpha 1.3galactosyltransferase. Immunogenetics. 41: 101–105.PubMedCrossRefGoogle Scholar
  47. Suzuki, E. and Naiki, M., 1984. Heterophile antibodies to rabbit erythrocytes in human sera and identification of the antigen as a glycolipid. J. Biochem., 95: 103–108.PubMedGoogle Scholar
  48. Tearle, R.G., Tange, M.J., Zannettino, Z.L., Katerelos, M., Shinkel, T.A., Van Denderen, B.J., Lonie, A.J., Lyons, I., Nottle, M.B., Cox, T., Becker, C., Peura, A.M., Wigley, P.L., Crawford, R.J., Robins, A.J., Pearse, M.J., and d’Apice, A.J., 1996, The α-1,3-galactosyltransferase knockout mouse. Implications for xenotransplantation, Transplantation, 61: 13–19.PubMedCrossRefGoogle Scholar
  49. Thall, A., Etienne-Decerf, J., Winand, R.J., and Galili, U., 1991a, The α-galactosyl epitope on mammalian thyroid cells, Acta Endocrinologica, 124: 692–699.PubMedGoogle Scholar
  50. Thall, A., Etienne-Decerf, J., Winand, R.J., and Galili, U., 1991b, The α-galactosyl epitope on human normal and autoimmune thyroid cells: possible relationship to autoimmunity, Autoimmunity, 10: 81–87.PubMedCrossRefGoogle Scholar
  51. Thall, A., Murphy, H., and Lowe, J.B., 1996, α1,3-galactosyltransferase deficient mice produce cytotoxic natural anti-Gal antibodies. Transplantation Proceedings, 28:561–62.Google Scholar
  52. Tybulewicz VL, Crawford CE, Jackson PK, Branson RT, and Mulligan, R.C., 1991, Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene, Cell, 65:1153–1163.PubMedCrossRefGoogle Scholar
  53. Vanhove, B., Goret, F., Soulillou, J.P., and Pourcel, C., 1997, Porcine alphα 1,3-galactosyltransferase: tissue-specific and regulated expression of splicing isoforms, Biochim Biophys Acta, 1356: 1–11.PubMedCrossRefGoogle Scholar
  54. Vaughan, H.A., Loveland, B.E., and Sandrin, M.S., 1994, Gal a(l,3)Gal is the major xenoepitope expressed on pig endothelial cells recognized by naturally occurring cytotoxic human antibodies. Transplantation, 58: 879–882.PubMedCrossRefGoogle Scholar
  55. Wassarman, P. M., 1988, Zona pellucida glycoproteins, Ann. Rev. Biochem. 57, 415–22.PubMedCrossRefGoogle Scholar
  56. Williams, R.L., Hilton, D.J., Pease, S., Willson, T.A., Stewart, C.L., Gearing, D.P., Wagner, E.F., Metcalf, D., Nicola, N.A., and Gough, N.M., 1988, Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells, Nature, 336:684–687.PubMedCrossRefGoogle Scholar
  57. Wong, W., Morris, P.J., and Wood, K.J., 1996, Syngeneic bone marrow expressing a single donor class I MHC molecule permits acceptance of a fully allogeneic cardiac allograft. Transplantation, 62:1462–1468.PubMedCrossRefGoogle Scholar
  58. Yamamoto, F.-i., Clausen, H., White, T., Marken, J., and Hakamori, S.-i., 1990, Molecular genetic basis of the histo-blood group ABO system. Nature, 345: 229–233.PubMedCrossRefGoogle Scholar
  59. Yong, Y.-G., de Goma, E., Ohdan, H., Bracy, J.L., Xu, Y., lacomini, J., Thall, A.D., and Sykes, M., 1998, Tolerization of anti-Galα 1–3Gal natural antibody-forming B cells by induction of mixed chimerism, J. Exp. Med., 187: 1335–1342.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Aron D. Thall
    • 1
  1. 1.BioTransplant, Inc.CharlestownUSA

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