Abstract
Our ability to genetically manipulate the mouse has had a great impact on medical research over the last few decades. Mouse genetics has developed into a powerful tool for dissecting the genetic causes of human disease and identifying potential targets for pharmaceutical intervention. With the recent sequencing of the human and mouse genomes, a large number of novel genes have been identified whose function in normal and disease physiology remains largely unknown. Government-sponsored multinational efforts are underway to analyze the function of all mouse genes through mutagenesis and phenotyping, making the mouse the interpreter of the human genome. A number of technologies are available for the generation of mutant mice, including gene targeting, gene trapping and transposon, chemical or radiation-induced mutagenesis. In this chapter, we review the current status of gene trapping technology, including its applicability to conditional mutagenesis.
Access provided by Autonomous University of Puebla. Download to read the full chapter text
Chapter PDF
Similar content being viewed by others
References
Austin CP, Battey JF, Bradley A, Bucan M, Capecchi M, Collins FS, Dove WF, Duyk G, Dymecki S, Eppig JT, Grieder FB, Heintz N, Hicks G, Insel TR, Joyner A, Koller BH, Lloyd KC, Magnuson T, Moore MW, Nagy A, Pollock JD, Roses AD, Sands AT, Seed B, Skarnes WC, Snoddy J, Soriano P, Stewart DJ, Stewart F, Stillman B, Varmus H, Varticovski L, Verma IM, Vogt TF, von Melchner H, Witkowski J, Woychik RP, Wurst W, Yancopoulos GD, Young SG, Zambrowicz B (2004) The knockout mouse project. Nat Genet 36:921–924
Auwerx J, Avner P, Baldock R, Ballabio A, Balling R, Barbacid M, Berns A, Bradley A, Brown S, Carmeliet P, Chambon P, Cox R, Davidson D, Davies K, Duboule D, Forejt J, Granucci F, Hastie N, de Angelis MH, Jackson I, Kioussis D, Kollias G, Lathrop M, Lendahl U, Malumbres M, von Melchner H, Muller W, Partanen J, Ricciardi-Castagnoli P, Rigby P, Rosen B, Rosenthal N, Skarnes B, Stewart AF, Thornton J, Tocchini-Valentini G, Wagner E, Wahli W, Wurst W (2004) The European dimension for the mouse genome mutagenesis program. Nat Genet 36:925–927
Bradley A, Hasty P, Davis A, Ramirez-Solis R (1992) Modifying the mouse: design and desire. Biotechnology (N Y) 10:534–539
Brown SD, Peters J (1996) Combining mutagenesis and genomics in the mouse — closing the phenotype gap. Trends Genet 12:433–435
Chang W, Hubbard SC, Friedel C, Ruley HE (1993) Enrichment of insertional mutants following retrovirus gene trap selection. Virology 193:737–747
Chennathukuzhi V, Stein JM, Abel T, Donlon S, Yang S, Miller JP, Allman DM, Simmons RA, Hecht NB (2003) Mice deficient for testis-brain RNA-binding protein exhibit a coordinate loss of TRAX, reduced fertility, altered gene expression in the brain, and behavioral changes. Mol Cell Biol 23:6419–6434
Dahl JP, Wang-Dunlop J, Gonzales C, Goad ME, Mark RJ, Kwak SP (2003) Characterization of the WAVE1 knock-out mouse: implications for CNS development. J Neurosci 23:3343–3352
Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A 100:4162–4167
Friedel RH, Plump A, Lu X, Spilker K, Jolicoeur C, Wong K, Venkatesh TR, Yaron A, Hynes M, Chen B, Okada A, McConnell SK, Rayburn H, Tessier-Lavigne M (2005) Gene targeting using a promoterless gene trap vector (“targeted trapping”) is an efficient method to mutate a large fraction of genes. Proc Natl Acad Sci U S A 102:13188–13193
Friedrich G S P (1991) Promoter traps in embryonic stem cells: a genetic screen to identify and mutate developmental genes in mice. Genes Dev 5:1513–1523
Gogos JA T R, Lowry W, Sloane BF, Weintraub H, Horwitz MJ (1996) Gene trapping in differentiating cell lines: regulation of the lysosomal protease cathepsin B in skeletal myoblast growth and fusion. J Cell Biol 134:837–847
Gossler AJA, Rossant J, Skarnes WC (1989) Mouse embryonic stem cells and reporter constructs to detect developmentally regulated genes. Science 244:463–465
Guo G, Wang W, Bradley A (2004) Mismatch repair genes identified using genetic screens in Blm-deficient embryonic stem cells. Nature 429:891–895
Hansen J, Floss T, Van Sloun P, Fuchtbauer EM, Vauti F, Arnold HH, Schnutgen F, Wurst W, von Melchner H, Ruiz P (2003) A large-scale, gene-driven mutagenesis approach for the functional analysis of the mouse genome. Proc Natl Acad Sci U S A 100:9918–9922
Hansen TV, Hammer NA, Nielsen J, Madsen M, Dalbaeck C, Wewer UM, Christiansen J, Nielsen FC (2004) Dwarfism and impaired gut development in insulin-like growth factor II mRNA-binding protein 1-deficient mice. Mol Cell Biol 24:4448–4464
Hasty P, Ramirez-Solis R, Krumlauf R, Bradley A (1991) Introduction of a subtle mutation into the Hox-2.6 locus in embryonic stem cells. Nature 350:243–246
Hicks GG S E, Li XM, Li CH, Pawlak M, Ruley HE (1997) Functional genomics in mice by tagged sequence mutagenesis. Nat Genet 16:338–344
Hubbard SC W L, Ruley HE, Muchmore EA (1994) Generation of Chinese hamster ovary cell glycosylation mutants by retroviral insertional mutagenesis. J Biol Chem 269:3717–3724
Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM (2000) Fate of the mammalian cardiac neural crest. Development 127:1607–1616
Joyner AL (2000) Gene targeting: A practical approach. Oxford University Press, Oxford, England
Kim JE, Li S, GrandPre T, Qiu D, Strittmatter SM (2003) Axon regeneration in young adult mice lacking Nogo-A/B. Neuron 38:187–199
Kim JY, Kang YS, Lee JW, Kim HJ, Ahn YH, Park H, Ko YG, Kim S (2002) p38 is essential for the assembly and stability of macromolecular tRNA synthetase complex: implications for its physiological significance. Proc Natl Acad Sci U S A 99:7912–7916
Kramerova I, Kudryashova E, Tidball JG, Spencer MJ (2004) Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro. Hum Mol Genet 13:1373–1388
Kuhnert F, Stuhlmann H (2004) Identifying early vascular genes through gene trapping in mouse embryonic stem cells. Curr Top Dev Biol 62:261–281
Lamia KA, Peroni OD, Kim YB, Rameh LE, Kahn BB, Cantley LC (2004) Increased insulin sensitivity and reduced adiposity in phosphatidylinositol 5-phosphate 4-kinase beta-/-mice. Mol Cell Biol 24:5080–5087
Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann N, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921
Leighton PA, Mitchell KJ, Goodrich LV, Lu X, Pinson K, Scherz P, Skarnes WC, Tessier-Lavigne M (2001) Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature 410:174–179
Li B, Dedman JR, Kaetzel MA (2003) Intron disruption of the annexin IV gene reveals novel transcripts. J Biol Chem 278:43276–43283
Li J, Zhu X, Chen M, Cheng L, Zhou D, Lu MM, Du K, Epstein JA, Parmacek MS (2005) Myocardin-related transcription factor B is required in cardiac neural crest for smooth muscle differentiation and cardiovascular development. Proc Natl Acad Sci U S A 102:8916–8921
Li L, Cohen SN (1996) Tsg101: a novel tumor susceptibility gene isolated by controlled homozygous functional knockout of allelic loci in mammalian cells. Cell 85:319–329
Liu J, Zhang L, Wang D, Shen H, Jiang M, Mei P, Hayden PS, Sedor JR, Hu H (2003) Congenital diaphragmatic hernia, kidney agenesis and cardiac defects associated with Slit3-deficiency in mice. Mech Dev 120:1059–1070
Mansour SL, Thomas KR, Capecchi MR (1988) Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature 336:348–532
Migliorini D, Denchi EL, Danovi D, Jochemsen A, Capillo M, Gobbi A, Helin K, Pelicci PG, Marine JC (2002) Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development. Mol Cell Biol 22:5527–5538
Miller BC, Eckman EA, Sambamurti K, Dobbs N, Chow KM, Eckman CB, Hersh LB, Thiele DL (2003) Amyloid-beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo. Proc Natl Acad Sci U S A 100:6221–6226
Niwa H A K, Kimura S, Taniguchi S, Wakasugi S, Yamamura K.J (1993) An efficient gene-trap method using poly A trap vectors and characterization of gene-trap events. Biochemistry (Tokyo) 113:343–349
Nonn L, Williams RR, Erickson RP, Powis G (2003) The absence of mitochondrial thioredoxin 2 causes massive apoptosis, exencephaly, and early embryonic lethality in homozygous mice. Mol Cell Biol 23:916–922
O’Kane CJGW (1987) Detection in situ of genomic regulatory elements in Drosophila. Proc Natl Acad Sci U S A 84:9123–9127
Pederson BA, Chen H, Schroeder JM, Shou W, DePaoli-Roach AA, Roach PJ (2004) Abnormal cardiac development in the absence of heart glycogen. Mol Cell Biol 24:7179–7187
Ramirez-Solis R, Liu P, Bradley A (1995) Chromosome engineering in mice. Nature 378:720–724
Schnutgen F, de Zolt S, van Sloun P, Hollatz M, Floss T, Hansen J, Altschmied J, Seisenberger C, Ghyselinck NB, Ruiz P, Chambon P, Wurst W, von Melchner H (2005) Genomewide production of multipurpose alleles for the functional analysis of the mouse genome. Proc Natl Acad Sci U S A 102:7221–7226
Silver J, Keerikatte V (1989) Novel use of polymerase chain reaction to amplify cellular DNA adjacent to an integrated provirus. J Virol 63:1924–1928
Skarnes WCAB, Joyner AL (1992) A gene trap approach in mouse embryonic stem cells: the lacZ reported is activated by splicing, reflects endogenous gene expression, and is mutagenic in mice. Genes Dev 6:903–918
Skarnes WCMJ, Hurtley SM, Beddington RS (1995) Capturing genes encoding membrane and secreted proteins important for mouse development. Proc Natl Acad Sci U S A 92:6592–6596
Steel M M J, Clark KA, Kearns IR, Davies CH, Morris RG, Skarnes WC, Lathe R (1998) Gene-trapping to identify and analyze genes expressed in the mouse hippocampus. Hippocampus 8:444–457
Tanaka H, Iguchi N, Toyama Y, Kitamura K, Takahashi T, Kaseda K, Maekawa M, Nishimune Y (2004) Mice deficient in the axonemal protein Tektin-t exhibit male infertility and immotile-cilium syndrome due to impaired inner arm dynein function. Mol Cell Biol 24:7958–7964
Varmus H (1988) Retroviruses. Science 240:1427–1435
Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, Gocayne JD, Amanatides P, Ballew RM, Huson DH, Wortman JR, Zhang Q, Kodira CD, Zheng XH, Chen L, Skupski M, Subramanian G, Thomas PD, Zhang J, Gabor Miklos GL, Nelson C, Broder S, Clark AG, Nadeau J, McKusick VA, Zinder N, Levine AJ, Roberts RJ, Simon M, Slayman C, Hunkapiller M, Bolanos R, Delcher A, Dew I, Fasulo D, Flanigan M, Florea L, Halpern A, Hannenhalli S, Kravitz S, Levy S, Mobarry C, Reinert K, Remington K, Abu-Threideh J, Beasley E, Biddick K, Bonazzi V, Brandon R, Cargill M, Chandramouliswaran I, Charlab R, Chaturvedi K, Deng Z, Di Francesco V, Dunn P, Eilbeck K, Evangelista C, Gabrielian AE, Gan W, Ge W, Gong F, Gu Z, Guan P, Heiman TJ, Higgins ME, Ji RR, Ke Z, Ketchum KA, Lai Z, Lei Y, Li Z, Li J, Liang Y, Lin X, Lu F, Merkulov GV, Milshina N, Moore HM, Naik AK, Narayan VA, Neelam B, Nusskern D, Rusch DB, Salzberg S, Shao W, Shue B, Sun J, Wang Z, Wang A, Wang X, Wang J, Wei M, Wides R, Xiao C, Yan C et al (2001) The sequence of the human genome. Science 291:1304–1351
Vidal F, Lopez P, Lopez-Fernandez LA, Ranc F, Scimeca JC, Cuzin F, Rassoulzadegan M (2001) Gene trap analysis of germ cell signaling to Sertoli cells: NGF-TrkA mediated induction of Fra1 and Fos by post-meiotic germ cells. J Cell Sci 114:435–443
Voss AK, Thomas T, Gruss P (1998) Efficiency assessment of the gene trap approach. Dev Dyn 212:171–180
Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M, An P, Antonarakis SE, Attwood J, Baertsch R, Bailey J, Barlow K, Beck S, Berry E, Birren B, Bloom T, Bork P, Botcherby M, Bray N, Brent MR, Brown DG, Brown SD, Bult C, Burton J, Butler J, Campbell RD, Carninci P, Cawley S, Chiaromonte F, Chinwalla AT, Church DM, Clamp M, Clee C, Collins FS, Cook LL, Copley RR, Coulson A, Couronne O, Cuff J, Curwen V, Cutts T, Daly M, David R, Davies J, Delehaunty KD, Deri J, Dermitzakis ET, Dewey C, Dickens NJ, Diekhans M, Dodge S, Dubchak I, Dunn DM, Eddy SR, Elnitski L, Emes RD, Eswara P, Eyras E, Felsenfeld A, Fewell GA, Flicek P, Foley K, Frankel WN, Fulton LA, Fulton RS, Furey TS, Gage D, Gibbs RA, Glusman G, Gnerre S, Goldman N, Goodstadt L, Grafham D, Graves TA, Green ED, Gregory S, Guigo R, Guyer M, Hardison RC, Haussler D, Hayashizaki Y, Hillier LW, Hinrichs A, Hlavina W, Holzer T, Hsu F, Hua A, Hubbard T, Hunt A, Jackson I, Jaffe DB, Johnson LS, Jones M, Jones TA, Joy A, Kamal M, Karlsson EK et al (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420:520–562
Wiles MV V F, Otte J, Fuchtbauer EM, Ruiz P, Fuchtbauer A, Arnold HH, Lehrach H, Metz T, von Melchner H, Wurst W (2000) Establishment of a gene-trap sequence tag library to generate mutant mice from embryonic stem cells. Nat Genet 24:13–14
Wilson C, Pearson RK, Bellen HJ, O’Kane CJ, Grossniklaus U, Gehring WJ (1989) P-element-mediated enhancer detection: an efficient method for isolating and characterizing developmentally regulated genes in Drosophila. Genes Dev 3:1301–1313
Xin HB, Deng KY, Shui B, Qu S, Sun Q, Lee J, Greene KS, Wilson J, Yu Y, Feldman M, Kotlikoff MI (2005) Gene trap and gene inversion methods for conditional gene inactivation in the mouse. Nucleic Acids Res 33:e14
Yang W, Musci TS, Mansour SL (1997) Trapping genes expressed in the developing mouse inner ear. Hear Res 114:53–61
You Y, Bergstrom R, Klemm M, Lederman B, Nelson H, Ticknor C, Jaenisch R, Schimenti J (1997) Chromosomal deletion complexes in mice by radiation of embryonic stem cells. Nat Genet 15:285–288
Yuan W, Rao Y, Babiuk RP, Greer JJ, Wu JY, Ornitz DM (2003) A genetic model for a central (septum transversum) congenital diaphragmatic hernia in mice lacking Slit3. Proc Natl Acad Sci U S A 100:5217–22
Yusa K, Horie K, Kondoh G, Kouno M, Maeda Y, Kinoshita T, Takeda J (2004) Genome-wide phenotype analysis in ES cells by regulated disruption of Bloom’s syndrome gene. Nature 429:896–899
Zambrowicz BP, Abuin A, Ramirez-Solis R, Richter LJ, Piggott J, BeltrandelRio H, Buxton EC, Edwards J, Finch RA, Friddle CJ, Gupta A, Hansen G, Hu Y, Huang W, Jaing C, Key BW Jr, Kipp P, Kohlhauff B, Ma ZQ, Markesich D, Payne R, Potter DG, Qian N, Shaw J, Schrick J, Shi ZZ, Sparks MJ, Van Sligtenhorst I, Vogel P, Walke W, Xu N, Zhu Q, Person C, Sands AT (2003) Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention. Proc Natl Acad Sci U S A 100:14109–14114
Zambrowicz BP, Friedrich GA, Buxton EC, Lilleberg SL, Person C, Sands AT (1998) Disruption and sequence identification of 2,000 genes in mouse embryonic stem cells. Nature 392:608–611
Zheng B, Ho C, Li S, Keirstead H, Steward O, Tessier-Lavigne M (2003) Lack of enhanced spinal regeneration in Nogo-deficient mice. Neuron 38:213–224
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Abuin, A., Hansen, G.M., Zambrowicz, B. (2007). Gene Trap Mutagenesis. In: Feil, R., Metzger, D. (eds) Conditional Mutagenesis: An Approach to Disease Models. Handbook of Experimental Pharmacology, vol 178. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-35109-2_6
Download citation
DOI: https://doi.org/10.1007/978-3-540-35109-2_6
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-35108-5
Online ISBN: 978-3-540-35109-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)