Advertisement

Transgenic Research

, Volume 9, Issue 4–5, pp 305–320 | Cite as

Transgenic animal bioreactors

  • Louis Marie Houdebine
Article

Abstract

The production of recombinant proteins is one of the major successes of biotechnology. Animal cells are required to synthesize proteins with the appropriate post-translational modifications. Transgenic animals are being used for this purpose. Milk, egg white, blood, urine, seminal plasma and silk worm cocoon from transgenic animals are candidates to be the source of recombinant proteins at an industrial scale. Although the first recombinant protein produced by transgenic animals is expected to be in the market in 2000, a certain number of technical problems remain to be solved before the various systems are optimized. Although the generation of transgenic farm animals has become recently easier mainly with the technique of animal cloning using transfected somatic cells as nuclear donor, this point remains a limitation as far as cost is concerned. Numerous experiments carried out for the last 15 years have shown that the expression of the transgene is predictable only to a limited extent. This is clearly due to the fact that the expression vectors are not constructed in an appropriate manner. This undoubtedly comes from the fact that all the signals contained in genes have not yet been identified. Gene constructions thus result sometime in poorly functional expression vectors. One possibility consists in using long genomic DNA fragments contained in YAC or BAC vectors. The other relies on the identification of the major important elements required to obtain a satisfactory transgene expression. These elements include essentially gene insulators, chromatin openers, matrix attached regions, enhancers and introns. A certain number of proteins having complex structures (formed by several subunits, being glycosylated, cleaved, carboxylated...) have been obtained at levels sufficient for an industrial exploitation. In other cases, the mammary cellular machinery seems insufficient to promote all the post-translational modifications. The addition of genes coding for enzymes involved in protein maturation has been envisaged and successfully performed in one case. Furin gene expressed specifically in the mammary gland proved to able to cleave native human protein C with good efficiency. In a certain number of cases, the recombinant proteins produced in milk have deleterious effects on the mammary gland function or in the animals themselves. This comes independently from ectopic expression of the transgenes and from the transfer of the recombinant proteins from milk to blood. One possibility to eliminate or reduce these side-effects may be to use systems inducible by an exogenous molecule such as tetracycline allowing the transgene to be expressed only during lactation and strictly in the mammary gland. The purification of recombinant proteins from milk is generally not particularly difficult. This may not be the case, however, when the endogenous proteins such as serum albumin or antibodies are abundantly present in milk. This problem may be still more crucial if proteins are produced in blood. Among the biological contaminants potentially present in the recombinant proteins prepared from transgenic animals, prions are certainly those raising the major concern. The selection of animals chosen to generate transgenics on one hand and the elimination of the potentially contaminated animals, thanks to recently defined quite sensitive tests may reduce the risk to an extremely low level. The available techniques to produce pharmaceutical proteins in milk can be used as well to optimize milk composition of farm animals, to add nutriceuticals in milk and potentially to reduce or even eliminate some mammary infectious diseases.

Recombinant proteins transgenic animals milk 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Adachi Y, Käs E and Laemmli UK (1989) Preferential, cooperative binding of DNA topoisomerase II to scaffold-associated regions. EMBO J 8: 3997–4006.PubMedGoogle Scholar
  2. Aigner B, Fleischmann M, Muller M and Brem G (1999) Stable long term germ-line transmission of transgene integration sites in mice. Transgenic Res 8: 1–8.PubMedGoogle Scholar
  3. Alton E, Griesenbach U and Geddes DM (1998) Milking gene therapy. Nature Sci 4: 1121–1122.Google Scholar
  4. Archer JS, Kennan WS, Gould MN and Bremel RD (1994) Human growth hormone (hGH) secretion in milk of goats after direct transfer of the hGH gene into the mammary gland by using replication-defective retrovirus vectors. Proc Natl Acad Sci USA 91: 6840–6844.PubMedGoogle Scholar
  5. Ashe HJ, Monks J, Wijgerde M, Fraser P, Proudfoot NJ (1997) Intergenic transcription and transinduction of the human b-globin locus. Genes Dev 11: 2494–2509.PubMedGoogle Scholar
  6. Attal J, Stinnakre MG, Théron MC, Terqui M and Houdebine LM (1997) The use of episomal vectors for transgenesis. In: Houdebine LM (ed.) Transgenic Animals: Generation and Use. (pp. 251–255). Harwood Academic Publishers, Amsterdam.Google Scholar
  7. Ayares D (1999) Gene targeting in livestock. Transgenic Research Conference, Tahoe City Aout 1999, 20.Google Scholar
  8. Baguisi A, Behboodi E, Melican DT, Pollock JS, Destrempes MM, Cammuso C, et al., (1999) Production of goats by somatic cell nuclear transfer. Nature Biotech 17: 456–461.Google Scholar
  9. Barash I, Faerman A, Richenstein M, Kari R, Damary G, Shani M and Bissell MJ (1999) In vivo and in vitro expression of human serum albumin genomic sequences in mammary epithelial cells with b-lactoglobulin and whey acidic protein promoters. Mol Repro Dev 52: 241–252.Google Scholar
  10. Bell AC and Felsenfeld G (1999) Stopped at the border: boundaries and insulators. Cur Opin Gene Dev 9: 191–198.Google Scholar
  11. Berdoz J, Tallichet Blanc C, Reinhardt M and Kraehenbuhl JP (1999) In vitro comparison of the antigen-binding and stability properties of the various molecular forms of IgA antibodies assembled and produced in CHO cells. Proc Natl Acad Sci USA 96: 3029–3034.PubMedGoogle Scholar
  12. Bishoff R, Degryse E, Perraud F, Dalemans W, Ali-Hadji D, Thépot D, et al., (1992) A 17.6 kbp region located upstream of the rabbit WAP gene directs high level expression of a functional human protein variant in transgenic mouse milk. FEBS Lett 305: 265–268.Google Scholar
  13. Blau HM and Rossi F (1999) Tet B or not tet B: advances in tetracycline-inducible gene expression. Proc Natl Acad Sci USA 96: 797–799.PubMedGoogle Scholar
  14. Bleck GT and Bremel RD (1994) Variation in expression of a bovine alpha-lactalbumin transgene in milk of transgenic mice. J Dairy Sci 77: 1897–1904.PubMedGoogle Scholar
  15. Bleck GT, White BR, Miller DJ and Wheeler MB (1998) Production of bovine α-lactalbumin in the milk of transgenic pigs. J Anim Sci 76: 3072–3078.PubMedGoogle Scholar
  16. Bosher JM and Labouesse M (2000) RNA interference: genetic wand and genetic watchdog. Nature Cell Biol 2: E31–E36.PubMedGoogle Scholar
  17. Bonifer C (1999) Long-distance chromatin mechanisms controlling tissue-specific gene locus activation. Gene 238: 277–289.PubMedGoogle Scholar
  18. Castilla J, Pintado B, Sola I, Sanchez-Morgado JM, Enjuanes L (1998) Engineering passive immunity in transgenic mice secreting virus-neutralizing antibodies in milk. Nature Biotech 16: 349–354.Google Scholar
  19. Cerdan MG, Young JI, Zino E, Falzone TL, Otero V, Torres HN and Rubinstein M (1998) Accurate spatial and temporal transgene expression driven by a 3.8-kilobase promoter of the bovine β-casein gene in the lactating mouse mammary gland. Mol Reprod Dev 49: 236–245.PubMedGoogle Scholar
  20. Chan AWS, Homan EJ, Ballou LU, Burns JC and Bremel RD (1998) Transgenic cattle produce reverse-transcribed gene transfer in oocytes. Proc Natl Acad Sci USA 95: 14028–14033.PubMedGoogle Scholar
  21. Chanat E, Martin P and Ollivier-Bousquet M (1999) αS1-casein is required for the efficient transport of β-and κ-casein from the endoplasmic reticulum to the Golgi apparatus of mammary epithelial cells. J Cell Sci. 112: 3399–3412.PubMedGoogle Scholar
  22. Clark AJ (1998) The mammary gland as a bioreactor: expression, processing and production of recombinant proteins. J Mamm Gland Biol Neop 3: 337–349.Google Scholar
  23. Cohen-Tannoudji M and Babinet C (1998) Beyond ‘knock-out’ mice: new perspectives for the programmed modification of the mammalian genome. Mol Hum Reprod 4: 929–938.PubMedGoogle Scholar
  24. Colman A (1996) Production of proteins in the milk of transgenic livestock: problems, solutions, and successes. Am J Clin Nutr 63: 639S–645S.PubMedGoogle Scholar
  25. Coulibaly S, Besenfelder U, Fleischmann M, Zinovieva N, Grossmann A, Wozny M, et al., (1999) Human nerve growth factor beta (hNGF-β): mammary gland specific expression and production in transgenic rabbits. FEBS Lett 444: 111–116.PubMedGoogle Scholar
  26. Dale TC, Krnacik MJ, Schmidhauser C, Yang CLQ, Bissell MJ and Rosen JM (1992) High level expression of the rat whey acidic protein gene is mediated by elements in the promoter and 3′ untranslated region. Mol Cell Biol 12: 905–914.PubMedGoogle Scholar
  27. De Groot N, Van Kuik-Romeijn P, Lee SH and De Boer H (1999) Over-expression of the murine polymeric immunoglobulin receptor gene in the mammary gland of transgenic mice. Transgenic Res 8: 125–135.PubMedGoogle Scholar
  28. Devinoy E, Thépot D, Stinnakre MG, Fontaine ML, Grabowski H, Puissant C, et al., (1994) High level production of human growth hormone in the milk of transgenic mice: the upstream region of the rabbit whey acidic protein (WAP) gene targets transgene expression to the mammary gland. Transgenic Res 3: 79–89.PubMedGoogle Scholar
  29. Di Tullio P, Cheng SH, Marshall J, Gregory RJ, Ebert KM, Maede HM and Smith AE (1992) Production of cystic fibrosis transmenbrane conductance regulator in the milk of transgenic mice. Bio/Tech 10: 74–77.Google Scholar
  30. Dobie KW, Lee M, Fantes JA, Graham E, Clark AJ, Springbett A, et al., (1996) Variegated transgene expression in mouse mammary gland is determined by the transgene integration locus. Proc Natl Acad Sci USA 93: 6659–6664.PubMedGoogle Scholar
  31. Dorsett D (1999) Distant liaisons: long-range enhancer-promoter interactions in Drosophila. Curr Opin Gene Dev 9: 505–514.Google Scholar
  32. Dorer DR (1997) Do transgene arrays form heterochromatin in vertebrates? Transgenic Res 6: 3–10.PubMedGoogle Scholar
  33. Draghia-Akli R, Fiorotto ML, Hill LA, Malone PB, Deaver DR and Schwartz RJ (1999) Myogenic expression of an injectable protease-resistant growth hormone-releasing hormone augments long-term growth in pigs. Nature Biotech 17: 1179–1183.Google Scholar
  34. Drews R, Paleyanda RK, Lee TK, Chang RR, Rehemtulla A, Kaufman RJ, et al., (1995) Proteolytic maturation of protein C upon engineering the mouse mammary gland to express furin. Proc Natl Acad Sci USA 92: 10462–10466.PubMedGoogle Scholar
  35. Dyck MK, Gagné D, Ouellet M, Sénéchal J, Bélanger E, Lacroix D, et al., (1999) Seminal vesicle production and secretion of growth hormone into seminal fluid. Nature Biotech 17: 1087–1090.Google Scholar
  36. Echelard Y (1997) Genetic mosaicism in the generation of transgenic mice. In: Houdebine LM (ed.) Transgenic Animals: Generation and Use. (pp. 233–235). Harwood Academic Publishers, Amsterdam.Google Scholar
  37. Echelard Y (1998) Increasing efficiency of transgenesis. Genetically engineering and cloning animals: Deer Valley Utah USA.Google Scholar
  38. Etches RJ, Clark ME, Verrinder Gibbins AM and Cochran MB (1997) Production of chimeric chickens as intermediates for gene transfer. Transgenic Animals: Generation and Use, Harwood Academic Publishers, Amsterdam, pp. 75–82.Google Scholar
  39. Etches R (1999) Avian embryonic stem cells and their application in the pharmaceutical and poultry industries. Transgenic Animal Research Conference Tahoe City USA 13.Google Scholar
  40. Eyestone WH (1998) Production and breeding of transgenic cattle using in vitro embryo production technology. Theriogeriology 51: 509–517.Google Scholar
  41. Fischer R, Schumann D, Zimmermann S, Drossard J, Sack M and Schillberg S (1999) Expression and characterization of bispecific single-chain Fv fragments produced in transgenic plants. Eur J Biochem 262: 810–816.PubMedGoogle Scholar
  42. Fire A (1999) RNA-triggered gene silencing. Trends Genet 15: 358–363.PubMedGoogle Scholar
  43. Fléchon JE (1997) What are ES cells? In: Houdebine LM (ed.) Transgenic Animals: Generation and Use (pp. 157–166). Harwood Academic Publishers, Amsterdam.Google Scholar
  44. Forrester WC, Fernandez LA, Grosschedl R (1999) Nuclear matrix attachment regions antagonize methylation-dependent repression of long-range enhancer promoter interactions. Gene Dev 13: 3003–3014.PubMedGoogle Scholar
  45. Forster K, Helbl V, Lederer T, Urlinger S, Wittenburg N, Hillen W (1999) Tetracycline-inducible expression systems with reduced basal activity in mammalian cells. Nucleic Acids Res 27: 708–710.PubMedGoogle Scholar
  46. Fox TD (1987) Natural variation in the genetic code. Ann Rev Genet 21: 67–91.PubMedGoogle Scholar
  47. Fujiwara Y, Takahashi R, Miwa M, Kameda M, Kodaira K, Hirabayashi M, et al., (1999a) Analysis of control elements for position independent expression of human α-lactalbumin YAC. Mol Reprod Dev 54: 17–23.PubMedGoogle Scholar
  48. Fujiwara Y, Miwa M, Takahashi R, Kodaira K, Hirabayashi M, Suzuki T and Ueda M (1999b) High-level expressing YAC vector for transgenic animal bioreactors. Mol Reprod Dev 52: 414–420.PubMedGoogle Scholar
  49. Fussenegger M, Bailey JE, Hauser H and Mueller PP (1999) Genetic optimization of recombinant glycoprotein production by mammalian cells. Trends Biotech 17: 35–42.Google Scholar
  50. Garrick D, Fiering S, Martin DIK and Whitelaw E (1998) Repeat-induced gene silencing in mammals. Nature Gen 18: 56–59.Google Scholar
  51. Gordon K, Lee E, Vitale JA, Smith AE, Westphal H and Hennighausen L (1987) Production of human tissue plasminogen activator in transgenic mouse milk. Bio/Technol 5: 1183–1187.Google Scholar
  52. Grabowski H, Le Bars D, Chene N, Attal J, Malienou-Ngassa R, Puissant C and Houdebine LM (1991) Rabbit whey acidic protein concentration in milk, serum, mammary gland extract, and culture medium. J Dairy Sci 74: 4143–4150.PubMedGoogle Scholar
  53. Günzburg WH, Salmons B, Zimmermann B, Müller M, Erfle V and Brem G (1991) A mammary specific promoter directs expression of growth hormone not only to the mammary gland, but also to Bergman Glia cells in transgenic mice. Mol Endocri 5: 123–133.Google Scholar
  54. Harris B (1999) Exploiting antibody-based technologies to manage environmental pollution. Trends Biotech 17: 290–296.Google Scholar
  55. Hirabayashi M, Kodaira K, Takahashi R, Sagara J, Suzuki T and Ueda M (1996) Transgene expression in mammary glands of newborn rats. Mol Reprod Dev 43: 145–149.PubMedGoogle Scholar
  56. Horowitz DS and Krainer AR (1994) Mechanisms for selecting 5′ splice sites in mammalian pre-mRNA splicing. Trends Genet 10: 100–106.PubMedGoogle Scholar
  57. Houdebine LM (1994) Production of pharmaceutical proteins from transgenic animals. J Biotech 34: 269–287.Google Scholar
  58. Houdebine LM (1998) The preparation of recombinant superoxide dismutases from the milk of transgenic animals. Mel Paris (ed.) Superoxide Dismutase: Recent advances and clinical applications (pp. 239–242).Google Scholar
  59. Houdebine LM and Attal J (1999) Internal ribosome entry sites (IRESs): reality and use. Transgenic Res 8: 157–177.PubMedGoogle Scholar
  60. Huang Y and Carmichael GG (1997) The mouse histone H2a gene contains a small element that facilitates cytoplasmic accumulation of intronless gene transcripts and of unspliced HIV-1-related mRNAs. Proc Natl Acad Sci USA 94: 10104–10109.PubMedGoogle Scholar
  61. Hyttinen JM, Peura T, Tolvanen M, Aalto J, Alhonen L, Sinervirta R, et al., (1994) Generation of transgenic dairy cattle from transgene analyzed and sexed embryos produced in vitro. Bio/Technol 12: 606–608.Google Scholar
  62. Ilan N, Barash I, Faerman A and Shani M (1996a) Dual regulation of β-lactoglobulin/human serum albumin gene expression by the extracellular matrix in mammary cells from transgenic mice. Exp Cell Res 224: 28–38.PubMedGoogle Scholar
  63. Ilan N, Barash I, Raikhinstein M, Faerman A and Shani M (1996b) β-lactoglobulin/human serum albumin fusion genes do not respond accurately to signals from the extracellular matrix in mammary epithelial cells from transgenic mice. Exp Cell Res 228: 146–159.PubMedGoogle Scholar
  64. Ivarie R (1999) Validating the Hen as a bioreactor for the production of exogenous proteins in egg whites. Transgenic Animal Research Conference Tahoe City USA, 22.Google Scholar
  65. John DCA, Watson R, Kind AJ, Scott AR, Kadler KE and Bulleid NJ (1999) Expression of an engineered form of recombinant procollagen in mouse milk. Nature Biotech 17: 385–389.Google Scholar
  66. Karatzas C, Zhou JF, Huang Y, Duguay F, Chretien N, Bhatia B, et al., (1999) Production of recombinant spider silk (biosteelTM) in the milk of transgenic animals. Transgenic Animal Research Conference Tahoe City USA, 34.Google Scholar
  67. Kerr DE, Furth PA, Powell AM, Wall RJ (1996) Expression of genegun injected plasmid DNA in the ovine mammary gland and in lymph nodes draining the injection site. Animal Biotech 7: 33–45.Google Scholar
  68. Kerr DE, Liang F, Bondioli KR, Zhao H, Kreibich G, Wall RJ and Sun T (1998) The bladder as a bioreactor: urothelium production and secretion of growth hormone into urine. Nature Biotech 16: 75–79.Google Scholar
  69. Kolb AF, Ansell R, McWhir J and Siddell SG (1999) Insertion of a foreign gene into the β-casein locus by Cre-mediated site-specific recombination. Gene 227: 21–31.PubMedGoogle Scholar
  70. Krimpenfort P, Rademakers A, Eyestone W, Van Der Schans A, Van Den Broek S, Kooiman P, et al., (1991) Generation of transgenic dairy cattle using ‘in vitro’ embryo production. Bio/Technol 9: 844–847.Google Scholar
  71. Kunita R, Samarut J and Pain B (1998) Establishment of the chicken gene-targeting disruption system. French Japonese Workshop. Genes and early development, June 4–5.Google Scholar
  72. Latham PW (1999) Therapeutic peptides revisited nature. Nature Biotech 17: 755–757.Google Scholar
  73. Lee WK, Kim SJ, Hong S, Lee T, Han Y, Yoo OJ, Im KS and Lee K (1998) Expression of a bovine β-casein/human lysozyme fusion gene in the mammary gland of transgenic mice. J Biochem Mol Biol 31: 413–417.Google Scholar
  74. Li X, Eastman EM, Schwartz RJ and Draghia-Akli R (1999) Synthetic muscle promoters: activities exceeding naturally occurring regulatory sequences. Nature Biotech 17: 241–245.Google Scholar
  75. Limonta J, Pedraza A, Rodriguez A, Freyre FM, Barral AM, Castro FO, et al., (1995) Production of active anti-CD6 mouse/human chimeric antibodies in the milk of transgenic mice. Immunotech 1: 107–113.Google Scholar
  76. Litscher ES, Liu C, Echelard Y and Wassarman PM (1999) Zona pellucida glycoprotein mZP3 produced in milk of transgenic mice is active as a sperm receptor, but can be lethal to newborns. Transgenic Res 8: 361–369.PubMedGoogle Scholar
  77. Lo D, Pursel V, Linton PJ, Sandgren E, Behringer R, Rexroad C, et al., (1991) Expression of mouse IgA by transgenic mice, pigs and sheep. Eur J Immunol 21: 1001–1006.PubMedGoogle Scholar
  78. Massoud M, Bischoff R, Dalemans W, Pointu H, Attal J, Schultz H, et al., (1991) Expression of active recombinant human alpha 1-antitrypsin in transgenic rabbits. J Biotech 18: 193–204.Google Scholar
  79. Massoud M, Attal J, Thépot D, Pointu H, Stinnakre MG, Theron MC, et al., (1996) The deleterious effects of human erythropoietin gene driven by the rabbit whey acidic protein gene promoter in transgenic rabbits. Reprod Nutr Dev 36: 555–563.PubMedGoogle Scholar
  80. McClenaghan M, Springbett A, Wallace RM, Wilde CJ and Clark J (1995) Secretory proteins compete for production in the mammary gland of transgenic mice. Biochem J 310: 637–641.PubMedGoogle Scholar
  81. McLaren A (2000) Establishment of the germ cell lineage in mammals. J Cell Physiol 182: 141–143.PubMedGoogle Scholar
  82. Meade H (1999) Taking ATIII from goats through clinical trials. Transgenic Animal Research Conference Tahoe City USA 33.Google Scholar
  83. Mendez MJ, Green LL, Corvalan JRF, Jia X, Maynard-Currie CE, Yang X, et al., (1997) Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nature Genet 15: 146–156.PubMedGoogle Scholar
  84. Mercier JC and Vilotte JL (1997) The modification of milk protein composition through transgenesis: progress and problems. In: Houdebine LM (ed.) Transgenic Animals Generation and Use. (pp. 473–482). Harwood Academic Publishers, Amsterdam.Google Scholar
  85. Mueller S, Prelle K, Rieger N, Petznek H, Lassnig C, Luksch U, Aigner B, Baetscher M, Wolf E, Mueller M and Brem G (1999) Mol Reprod Dev 54: 244–225PubMedGoogle Scholar
  86. Nagaraju J, Kanda T, Yukuhiro K, Chavancy G, Tamura T and Couble P (1996) Attempt at transgenesis of the silkworm (Bombyx mori L.) by egg-injection of foreign DNA. Appl Entomol Zool 31: 458–596.Google Scholar
  87. Naito M (1997) The microinjection of DNA into early chicken embryo. In: Houdebine LM (ed.) Transgenic Animals: Generation and Use. (pp. 69–73). Harwood Academic Publishers, Amsterdam.Google Scholar
  88. Niemann H, Halter R, Espanion G, Wrenzycki C, Herrmann D, Lemme E, et al., (1996) Expression of human blood clotting factor VIII (FVIII) constructs in the mammary gland of transgenic mice and sheep. J Anim Breed Genet 113: 437–444.Google Scholar
  89. Ninomiya T, Hirabayashi M, Sagara J and Yuki A (1994) Functions of milk protein gene 5′ flanking regions on human growth hormone gene. Mol Reprod Dev 37: 276–283.PubMedGoogle Scholar
  90. Oh KB, Choi H, Kang Y, Choi WS, Kim MO, Lee KS, Lee KK and Lee CS (1999) A hybrid bovine β-casein/bGH gene directs transgene expression to the lung and mammary gland of transgenic mice. Transgenic Res 8: 307–311.PubMedGoogle Scholar
  91. Page RL, Canseco RS, Russell CG, Johnson JL, Velander WH and Gwazdauskas FC (1995) Transgene detection during early murine embryonic development after pronuclear microinjection. Transgenic Res 4: 12–17.PubMedGoogle Scholar
  92. Paleyanda RK, Velander WH, Lee TK, Scandella DH, Gwazdauskas FC, Knight JW, et al., (1997) Transgenic pigs produce functional human factor VIII in milk. Nature Biotech 15: 971–975.Google Scholar
  93. Palmiter RD, Brinster RL, Hammer RE, Trumbauer ME, Rosenfeld MG, Birnberg NC and Evans RM (1982) Dramatic growth of mice that develop from eggs microinjected with metallothionein-growth hormone fusion genes. Nature 300: 611–615.PubMedGoogle Scholar
  94. Palmiter RD, Sandgren EP, Avarbock MR, Allen DD and Brinster RL (1991) Heterologous introns can enhance expression of transgenes in mice. Proc Natl Acad Sci USA 88: 478–482.PubMedGoogle Scholar
  95. Perry ACF, Wakayama T, Kishikawa H, Kasai T, Okabe M, Toyoda Y and Yanagimachi R (1999) Mammalian transgenesis by intracytoplasmic sperm injection. Science 284: 1180–1183.PubMedGoogle Scholar
  96. Petitclerc D, Attal J, Théron MC, Bearzotti M, Bolifraud P, Kann G, et al., (1995) The effect of various introns and transcription terminators on the efficiency of expression vectors in various cultured cell lines and in the mammary gland of transgenic mice. J Biotechnol 40: 169–178.PubMedGoogle Scholar
  97. Pinkaart MJ, Recillas-Targa F and Felsenfeld G (1998) Loss of transcriptional activity of a transgene is accompanied by DNA methylation and histone deacetylation and is prevented by insulators. Genes Dev 12: 2852–2862.Google Scholar
  98. Platenburg GJ, Kootwijk EP, Kooiman PM, Woloshuk SL, Nuijens JH, Krimpenfort PJ, et al., (1994) Expression of human lactoferrin in milk of transgenic mice. Transgenic Res 3: 99–108.PubMedGoogle Scholar
  99. Prieto PA, Mukerji P, Kelder B, Erney R, Gonzalez D, Yun JS, et al., (1995) Remodeling of mouse milk glycoconjugates by transgenic expression of a human glycosyltransferase. J Biol Chem 270: 29515–29519.PubMedGoogle Scholar
  100. Prunkard D, Cottingham I, Garner I, Bruce S, Dalrymple M, Lasser G, et al., (1996) High-level expression of recombinant human fibrinogen in the milk of transgenic mice. Nature Biotech 14: 867–871.Google Scholar
  101. Qureschi SA, Kim RM, Konteatis Z, Biazzo DE, Motamedi H, Rodrigues R, et al., (1999) Mimicry of erythoropoietin by a nonpeptide molecule. Proc Natl Acad Sci USA 96: 12156–12161.Google Scholar
  102. Recillas-Targa F, Bell AC and Felsenfeld G (1999) Positional enhancer-blocking activity of the chicken b-globin insulator in transiently transfected cells. Proc Natl Acad Sci USA 96: 14354–14359.PubMedGoogle Scholar
  103. Reddy VB, Vitale JA, Wei C, Montoya-Zavala M, Stice SL, Balise J and Robl JM (1991) Expression of human growth hormone in the milk of transgenic mice. Animal Biotech 2: 15–29.Google Scholar
  104. Rijnkels M, Miller W and Rosen JM (1999) Casein Gene locus control regions? Genet Anal Bio-mol Eng (in press).Google Scholar
  105. Robl JM (1999) New life for sperm-mediated transgenesis? Nature Biotech 17: 636–637.Google Scholar
  106. Rokkones E, Fromm SH, Kareem BN, Klungland H, Olstad OK, Hogset A, et al., (1995) Human parathyroid hormone as a secretory peptide in milk of transgenic mice. J Cell Biochem 59: 168–176.PubMedGoogle Scholar
  107. Ronfort C, Legras C and Verdier G (1997) The use of retroviral vectors for gene transfer into bird embryo. In: Houdebine LM (ed.) Transgenic Animals: Generation and Use. (pp. 83–94). Harwood Academic Publishers, Amsterdam.Google Scholar
  108. Rosen JM, Li S, Raught B and Hadsell D (1996) The mammary gland as a bioreactor: factors regulating the efficient expression of milk protein-based transgenes. Am J Clin Nutr 63: 627S–632S.PubMedGoogle Scholar
  109. Rucker EB and Piedrahita JA (1997) Cre-mediated recombination at the murine whey acidic protein (mWAP) locus. Mol Reprod Dev 48: 324–331.PubMedGoogle Scholar
  110. Rudolph NS (1999) Biopharmaceutical production in transgenic livestock. Trends Biotech 17: 367–374.Google Scholar
  111. Saif LJ and Wheeler MB (1998) WAPping gastroenteritis with transgenic antibodies. Nature Biotech 16: 334–335.Google Scholar
  112. Santoso B, Ortiz BD, Winoto A (2000) Control of organ-specific demethylation by an element of the T-cell receptor-locus control region. J Biol Chem 275: 1952–1958.PubMedGoogle Scholar
  113. Schnieke AE, Kind AJ, Ritchie WA, Mycock K, Scott AR, Ritchie M, et al., (1997) Human factor IX transgenic sheep produced by transfer of nuclei from transfected fetal fibroblasts. Science 278: 2131–2133.Google Scholar
  114. Shamay A, Pursel VG, Wilkinson E, Wall RJ and Hennighausen L (1992) Expression of the whey acidic protein in transgenic pigs impairs mammary development. Transgenic Res 1: 124–132.PubMedGoogle Scholar
  115. Sharma A, Martin MJ, Okabe JF, Truglio RA, Dhanjal NK, Logan JS and Kumar R (1994) An isologous porcine promoter permits high level expression of human hemoglobin in transgenic swine. Bio/Technol 12: 55–59.Google Scholar
  116. Sherman A, Dawson A, Mather C, Gihooley H, Mitchell R, Finnegan D and Sang H (1998) Transposition of the drosophila element mariner into the chicken germ line. Nature Biotech 16: 1050–1053.Google Scholar
  117. Simons JP, McClenaghan M and Clark AJ (1987) Alteration of the quality of milk by expression of sheep beta-lactoglobulin in transgenic mice. Nature 328: 530–532.PubMedGoogle Scholar
  118. Sippel AE, Saueressig H, Huber MC, Faust N and Bonifer C (1997) Insulation of transgenes from chromosomal position effects. In: Houdebine LM (ed.) Transgenic Animals: Generation and Use. (pp. 257–265). Harwood Academic Publishers, Amsterdam.Google Scholar
  119. Sohn BH, Kim SJ, Park H, Park SK, Lee SC, Hong HJ, et al., (1999) Expression and characterization of bioactive human thrombopoietin in the milk of transgenic mice. DNA Cell Biol 18: 845–852.PubMedGoogle Scholar
  120. Sola I, Castilla J, Pintado B, Sanchez-Morgado JM, Whitelaw CBA, Clark AJ and Enjuanes L (1998) Transgenic mice secreting coronavirus neutralizing antibodies into the milk. J Virol 72: 3762–3772.PubMedGoogle Scholar
  121. Somia NV, Kafri T and Verma IM (1999) Piecing together more efficient gene expression. Nature Biotech 17: 224–245.Google Scholar
  122. Soulier S, Stinnakre MG, Lepourry L, Mercier JC, Vilotte JL (1999) Use of doxycycline-controlled gene expression to reversibly alter milk-protein composition in transgenic mice. Eur J Biochem 260: 533–539.PubMedGoogle Scholar
  123. Stinnakre MG, Devinoy E, Thépot D, Chêne N, Bayat-Samardi M, Grabowski H and Houdebine LM (1992) Quantitative collection of milk and active recombinant proteins from the mammary glands of transgenic mice. Anim Biotech 3: 245–255.Google Scholar
  124. Stinnakre MG, Soulier S, Schibler L, Lepourry L, Mercier JC and Vilotte JL (1999) Position-independent and copy number related expression of a goat bacterial artificial chromosome α-lactalbumin gene in transgenic mice. Biochem J 339: 33–36.PubMedGoogle Scholar
  125. Strömqvist M, Törnell J, Edlund M, Edlund A, Johansson T, Lindgren K, et al., (1996) Recombinant human bile salt-stimulated lipase: an example of defective O-glycosylation of a protein produced in milk of transgenic mice. Transgenic Res 5: 475–485.PubMedGoogle Scholar
  126. Strömqvist M, Houdebine LM, Andersson J, Edlund A, Johansson T, Viglietta C, et al., (1997) Recombinant human extracellular superoxide dismutase produced in milk of transgenic rabbits. Transgenic Res 6: 271–278.PubMedGoogle Scholar
  127. Taboit-Dameron F, Malassagne B, Viglietta C, Puissant C, Leroux-Coyau M, Chereau C, et al., (1999) Association of the 5′HS4 sequence of the chicken beta-globin locus control region with human EF1 alpha gene promoter induces ubiquitous and high expresssion of human CD55 and CD59 cDNAs in transgenic rabbits. Transgenic Res 8: 223–235.PubMedGoogle Scholar
  128. Tamura T, Thibert C, Royer C, Kanda T, Abraham E, Kamba M, et al., (1999) Germline transformation of the silkworm Bombyx mori L. using a piggyBac transposon-derived vector. Nature Biotech 18: 81–84.Google Scholar
  129. Thépot D, Devinoy E, Fontaine ML, Stinnakre MG, Massoud M, Kann G and Houdebine LM (1995) Rabbit whey acidic protein gene upstream region controls high-level expression of bovine growth hormone in the mammary gland of transgenic mice. Mol Reprod Dev 42: 261–267.PubMedGoogle Scholar
  130. Tojo H, Tanaka S, Matsuzawa A, Takahashi M and Tachi C (1993) Production and characterization of transgenic mice expressing a hGH fusion gene driven by the promoter of mouse whey acidic protein (mWAP) putatively specific to mammary gland. J Reprod Dev 39: 145–155.Google Scholar
  131. Tomizuka K, Yoshida H, Uejima H, Kugoh H, Sato K, Ohguma A, et al., (1997) Functional expression and germline transmission of a human chromosome fragment in chimaeric mice. Nature Genetics 16: 133–143.PubMedGoogle Scholar
  132. Travers A (1999) Chromatin modification by DNA tracking. Proc Natl Acad Sci 96: 13634–13637.PubMedGoogle Scholar
  133. Van Cott KE, Williams B, Velander WH, Gwazdauskas F, Lee T, Lubon H, Drohan WN (1996) Affinity purification of biologically active and inactive forms of recombinant human protein C produced in porcine mammary gland. J Mol Recognit 9: 407–414.PubMedGoogle Scholar
  134. Verrinder-Gibbins AM (1998) The chicken, the egg, and the ancient mariner. Nature Biotech 16: 1013–1014.Google Scholar
  135. Vos JH (1998) Mammalian artificial chromosomes as tools for gene therapy. Curr Opin Genet Dev 8: 351–359.PubMedGoogle Scholar
  136. Wagner K, Wall RJ, St Onge L, Gruss P, Wynshaw-Boris A, Garrett L, et al., (1997) Cre-mediated gene deletion in the mammary gland. Nucleic Acids Res 25: 4323–4330.PubMedGoogle Scholar
  137. Wall RJ (1999) Biotechnology for the production of modified and innovative animal products: transgenic livestock bioreactors. Lives Prod Sci 59: 243–255.Google Scholar
  138. Walters MC, Magis W, Fiering S, Eidemiller, Scalzo D, Groudine M and Martin DIK (1996) Transcriptional enhancers act in cis to suppress position-effect variegation. Genes Dev 10: 185–195.PubMedGoogle Scholar
  139. Wang Y, DeMayo FJ, Tsai SY and O'Malley BW (1996) Ligand-inducible and liver-specific target gene expression in transgenic mice. Nature Biotech 15: 239–243.Google Scholar
  140. Weidle UH, Lenz H and Brem G (1991) Genes encoding a mouse monoclonal antibody are expressed in transgenic mice, rabbits and pigs. Gene 98: 185–191.PubMedGoogle Scholar
  141. Wen J, Kawamata Y, Tojo H, Tanaka S and Tachi C (1995) Expression of whey acidic protein (WAP) genes in tissues other than the mammary gland in normal and transgenic mice expressing mWAP/hGH fusion gene. Mol Reprod Dev 41: 399–406.PubMedGoogle Scholar
  142. Wheeler M (1999) Transgenic alteration of sow milk: production and characterization bovine a-lactalbumin and IGF-I transgenic swine. Transgenic Animal Research Conference Tahoe City USA, 28–29.Google Scholar
  143. Whitelaw B, Harris S, McClenaghan M and Simons JP (1992) Position-independent expression of the ovine b-lactoglobulin gene in transgenic mice. Biochem J 286: 31–39.PubMedGoogle Scholar
  144. Whitelaw B (1999) Toward designer milk. Nature Biotech 17: 135–136.Google Scholar
  145. Willard FH (1998) Human artificial chromosomes coming into focus. Nature Biotech 16: 415–416.Google Scholar
  146. Wright G and Colman A (1997) Purification of recombinant proteins from sheep's milk. In: Houdebine LM (ed.) Transgenic Animals: Generation and Use. (pp. 469–471). Harwood Academic Publishers, Amsterdam.Google Scholar
  147. Wright A and Morrison SL (1997) Effect of glycosylation on antibody function: implications for genetic engineering. Trends Biotech 15: 26–32.Google Scholar
  148. Wright G, Carver A, Cottom D, Reeves D, Scott A, Simons P, et al., (1991) High level expression of active human alpha-1-antitrypsin in the milk of transgenic sheep. Bio/Techno 9: 830–834.Google Scholar
  149. Wrighton NC, Farrell FX, Chang R, Kashyap AK, Barbone FP, Mulcahy LS, et al., (1996) Small peptides as potent mimetics of the protein hormone erythropoietin. Science 273: 458–464.PubMedGoogle Scholar
  150. Yamao M, Katayama N, Nakazawa H, Yamakaws M, Hayashi Y, Hara S, et al., (1999) Gene targeting in the silkworm by use of a baculovirus. Genes Dev 13: 511–516.PubMedGoogle Scholar
  151. Yarus S, Rosen JM, Cole AM and Diamond G (1996) Production of active bovine tracheal antimicrobial peptide in milk of transgenic mice. Proc Natl Acad Sci USA 93: 14118–14121.PubMedGoogle Scholar
  152. Yull F, Binas B, Harold G, Wallace R and Clark AJ (1997) Transgene rescue in the mammary gland is associated with transcription but does not require translation of BLG transgenes. Transgenic Res 6: 11–17.PubMedGoogle Scholar
  153. Zinovieva N, Lassnig C, Schams D, Besenfelder U, Wolf E, Müller S, et al., (1998) Stable production of human insulin-like growth factor 1 (IGF-1) in the milk of hemi-and homozygous transgenic rabbits over several generations. Transgenic Res 7: 437–447.PubMedGoogle Scholar
  154. Zuelke KA (1998) Transgenic modification of cows milk for valueadded processing. Reprod Fertil Dev 10: 671–676.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Louis Marie Houdebine
    • 1
  1. 1.Unite de Biologie du Développement et BiotechnologieInstitut National de la Recherche AgronomiqueJouy-en-Josas CedexFrance

Personalised recommendations