Abstract
Gene targeting by homologous recombination in mouse embryonic stem cells is a powerful technique to determine the physiological function of any gene product in embryonic and postnatal development and in molecular pathogenesis. Although the technique is very demanding and still in its developing stage several knockout mice carrying disrupted genes, which were once thought important for the development or molecular pathogenesis of certain tissues, have given unexpected results. A gene/function redundancy or superfluous and on-functional theory has been advanced by many investigatiors to explain the unexpected results. These surprising results may teach us a new lesson and lead to a revision of the strongly held view that highly conserved and abundantly expressed genes have a prominent role and function in cell physiology and development Additional, they may also support the notion that molecular cross-talk among the genes may play an important role in determining the minimal phenotype.
Similar content being viewed by others
References
Hasty P, Ramiro R-S, Krumlauf R, Bradley A: Introduction of a subtle mutation in the hox-2.6 locus in embryonic stem cells. Nature 350: 243–246, 1991
Capecchi MR: Altering the genome by homologous recombination. Science 244: 1288–1292, 1989
Bueler H, Fisher M, Lang Y, Bluethaman H, Lipp HP, DeArmond SJ, Prusiner SB, Aguet M, Weissman C: Normal development and behavior of mice lacking the neuronal cell surface PrP protein. Nature 356: 577–582, 1992
Hooper M, Hardy K, Handyside A, Hunter S, Monk M: HPRT deficient (Lesch-Nyham) mouse embryos derived from germ line colonization by cultured cells. Nature 326: 292–295, 1987
Kuehn MR, Bradley A, Robertons EJ, Evans MJ: A potential animal model for Lesch-Nyhan syndrome through introduction of HPRT mutations into mice. Nature 326: 295–298, 1987
Collins FS, Wilson JM: A welcome animal model. Nature 358: 708–709, 1992
Snouwaert JN, Brigman KK, Latour AM, Malouf NN, Boucher RC, Smithies O, Koller BH: An animal model for cystic fibrosis made by gene targeting. Science 257: 1083–1088, 1992
Clarke LL, Grubb BR, Gabriel SE, Smithies O, Koller BH, Boucher RC: Defective epithelial chloride transport in a gene targeted mouse model of cystic fibrosis. Science 257: 1125–1128, 1992
Joyner AL, Herrup K, Auerback BA, Davis CA, Rossant J: Subtle cerebellar phenotype in mice homozygous for a targeted deletion of the En-2 homebox. Science 251: 1239–1243, 1991
Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomer CA Jr, Butel JS, Bradley A: Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature 356: 215–221, 1992
Zijlstra M, Box M, Simister NE, Loring JM, Raulet DH, Jaenish R, β2 microglobulin deficient mice lact CD4 8+ cytolytic T-cells. Nature 344: 742–746, 1990
Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, Curry CJ, Fernhoff PM, Grix AW Jr, Lott IT, Richard JM, Sun SC: Retinoic acid embryopathy. N Engl J Med 313: 837–841, 1985
Morriss Kay G: Retinoic acid and craniofacial development: molecules and morphogenesis. BioEssays 15: 9–15, 1993
Li En, Sucov HM, Lee KF, Evans RM, Jaenisch R: Normal development and growth of mice carrying a targeted disruption of the α-1 retinoic acid receptor gene. Proc Nat Acad Sci USA 90: 1590–1594, 1993
Gammon JV, Lane DP: p53 and DNA polymerase α compete for binding to SV40 T antigen. Nature 329: 456–458, 1987
Levine AJ, Momand J, Finlay CA: The p53 tumor suppressor gene. Nature 351: 453–456, 1991
Marshall CJ: Tumor suppressor genes. Cell 64: 313–326, 1991
Lane DP: A death in the life of p53. Nature 362: 786–787, 1993
Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T: p53 is required for radiation induced apoptosis in mouse thymocytes. Nature 362: 847–849, 1993
Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, Wyllie AH: Thymocytes apoptosis induced by p53 dependent and independent pathway. Nature 362: 849–852, 1993
LeMouellic H, Lallemand Y, Brulet P: Homeosis in the mouse induced by a null mutation in the hox-3.1 gene. Cell 69: 251–264, 1992
Tybulewicz VLJ, Crawford CE, Jackson PK, Bronson RT, Mulligan RC: Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl protooncogene. Cell 65: 1153–1163, 1991
Schwartzberg PL, Stall AM, Hardin JD, Bowdish KS, Humaran TS, Boast S, Harbison ML, Robertson EJ, Goff SP: Mice homozygous for the ablml mutation show poor viability and depetion of selected B and T cell populations. Cell 65: 1165–1175, 1991
Holland PWH, Hogan BLM: Expression of homeobox genes during mouse development: a review. Genes Dev 2: 773–782, 1988
Chisaka O, Capecchi MR: Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox genes hox-1.5 Nature 350: 473–479, 1991
Chisaka O, Musci TS, Capecchi MR: Development defects of the ear, cranial nerves and hindbrain resulting from targeted disruptiion of the mouse homeobox gene hox-1.6. Nature 355: 516–520 1992
Lufkin T, Dierch A, LeMeur M, Mark M, Chambon P: Disruption of the hox-1.6 homeobox gene results in defects in a region corresponding to its vostral domain of expression. Cell 66: 1105–1119, 1991
Braun T, Rudniki MA, Arnold HH, Jaenisch R: Targeted inactivation of the muscle regulatory gene myf-5 results in abnormal rib development and perinatal death. Cell 71: 369–382, 1992
Rudnicki MA, Braun T, Hinuma S, Jaenisch R: Inactivation of myoD in mice leads to upregulation of the myogenic HLH gene myf-5 and results in apparently normal muscle development. Cell 71: 383–390, 1992
Mann GB, Fowler KJ, Gabriel A, Nice EC, Williams L, Dunn RR: Mice with a null mutation of the TGFα gene have abnormal skin architecture, wavy hair and curly whiskers and often develop comeal inflammation. Cell 73: 249–261 1993
Luetteke NC, Qui TH, Pieffer RL, Oliver P, Smithies O, Lee DC: TGFα deficiency results in hair follicle and eye abnormalities in targeted wavedl mice. Cell 73: 263–268, 1993
Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, Annunziata N, Doestschman T: Targeted disruption of the mouse transforming growth factor β1 gene results in multifocal inflammatory disease. Nature 359: 693–699, 1992
Soriano P, Montgomery C, Geske R, Bradly A: Targeted disruption of the c-src protooncogene leads to osteopetrosis in mice. Cell 64: 693–702, 1991
Lee KF, Li E, Huber LJ, Landis SC, Sharpe AH, Chao ME, Jaenisch R: Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69: 737–749 1992
Baun T, Buschhausen DG, Bober E, Tannich E, Arnold HH: A novel human muscle factor related to but distinct from myO Dl induces myogenic conversion in 10Tl/2 fibroblasts. EMBO J 8: 701–709, 1989
Bernard JA, Lyons RM, Moses HL: The cell biology of transforming growth factor β. Biochim Biophys Acta 1032: 79–87, 1990
Horn WC, Neff L, Chatterjee D, Lomri A, Levy JB, Baron R: Osteoclasts express high level of pp60csrc in association with intracellular membranes. J Cell Biol 119: 1003–1013, 1992
Nowak R: c-src's cellular role astounds researchers: J NIH Res 3: 54–58, 1991
Beaulieu JF, Jutras S, Kusakabe M, Perreault, N: Expression of tenascin in the developing human small intestine. Biochem Biophys Res Comm 192: 1086–1092, 1993
Saga Y, Yagi T, Ikawa Y, Sakakura T, Aizawa S: Mice develop normally without tenascin. Genes Dev 6: 1821–1831, 1992
Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE: RAG-1 deficient mice have no mature band T lymphocytes. Cell 68: 869–877, 1992
Shinkai Y, Rathbun G, Lam K-P, Oltz EM, Stewart V, Mendelshohn M, Charron J, Datta M, Young F, Stall AM, Alt FW: RAG-2 deficient mice lack mature lymphocytes owing to inability to initiate V(D) J rearrangements. Cell 68: 855–867, 1992
Chun JJM, Schatz DG, Oettinger MA, Jaenisch R, Baltimore D: The re combination activation gene-1 (RAG-1) transcript is present in the murine central nervous system. Cell 64: 189–200, 1991
Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL: Severe hypercholestrerolemia and athoroslerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71: 343–353, 1992
Shimano H, Yamada N, Katsuki M, Shimada M, Gotoda T, Harada K, Murase T, Fukuzawa C, Takuku F, Yazaki Y, Piedrahita JA, Zhang SH, Hagaman HR, Oliver PM, Maeda N: Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Nat Acad Sci USA 89: 4471–4475, 1992
Erickson HP: Gene knockouts of c-src, transforming growth factor β-1 and tenascin suggests superfluous, non-functional expression of proteins: J Cell Biol 120: 1079–1081, 1993
Rossant J: Gene disruption in mammals. Curr Opinion in Genet Dv 1: 236–240, 1991
Tautz D: Redundancies, development and the flow of information: Bio Essays 14: 263–266, 1992
Brookfield J: Can genes be tryly redundant? Curr Biol 2: 553–554, 1992
Erickson RP: Why isn't a mouse more like a man? Trends Genet 5: 1–3, 1989
Davies K: Peripherin and the vision thing: Nature 362: 92 1993
Bueler H, Aguzzi A, Sailer A, Grenier RA, Autenried P, Aquet M, Weissmann C: Mice devoid of PrP are resistant to scrapie. Cell 73: 1339–1347, 1993
Appleby MW, Gross JA, Cooke MP, Levin SD, Qian X, Perlmutter RM: Defective T cell receptor signalling in mice lacking the thymic isoform of p59fyn. Cell 70: 751–763, 1992
Stein PL, Lee HM, Rich S, Soriano P. pp59fyn mutant mice display differential signalling in thymocyte and peripheral T cells. Cell 70: 741–750, 1992
Grant SGN, O'Dell TI, Karl KA, Stein PL, Soriano P, Kandel ER: Impaired long-term potentiation, spatial learning and hippocampal development in fyn mutant mice. Science 258: 1903–1910, 1992
Molina TJ, Kishihara K, Siderovski DP, Van Ewijk W, Nerendran A, Timms E, Wakeham A, Paige CJ, Hartmann KV, Veillette A, Davidson D, Mak TW: Profound block in thymocyte development in mice lacking p56kk. Nature 357: 161–164, 1992
Imamoto A, Soriano P: Disruption of the csk gene encoding a negative regulator of Src family tyrosine kinases leads to neural tube defects and embryonic lethality in mice. Cell 73: 1117–1124, 1993
Nada S, Yagi T, Takeda H, Tokunaga T, Nakagawa H, Ikawa Y, Okada M, Aizawa S: Constitutive activation of Src family kinases in mouse embryos that lack csk. Cell 73: 1125–1135, 1993
Giese KP, Martini R, Lemke G, Soriano P, Schachner M: Mouse Po gene disruption leads to hypomyelination, abnormal expression of recognition molecules and degeneration of myelin and axons. Cell 71: 565–576, 1992
Johnson RS, Spiegelman BM, Papaioannou V: Pleiotropic effects of a null mutation in the c-fos protooncogene. Cell 71: 577–586, 1992
Luc van Kaer, Aston-Rickardt PG, Ploegh HL, Tonegawa S: TAP 1 mutant mice are deficient in antigen presentation, surface class 1 molecules and CD4 8+ T cells. Cell 71: 1205–1214, 1992
Li, En, Bestor TH, Jaenisch R: Targeted mutation of the DNA methyltransferase gene result in embryonic lethality. Cell 69: 915–926, 1992
Viville S, Neefjues J, Lotteau V, Dierich A, Lemeur M, Ploegh H, Benoist C, Mathis D: Mice lacking the MHC Class II-associated invariant chain. Cell 72: 635–648, 1993
Ramierez-Solis R, Zheng H, Whiting J, Krumlauf R, Bradley A: Hoxb-4 (hox-2.6) mutant mice show homeotic transformation of a cervical vertebra and defects in the closure of the sternal rudiments. Cell 73: 279–294, 1993
Pfeffer K, Matsuyama T, Kundig TM, Wakeham A, Kishihara K, Shahinian A, Wiegmann K, Ohashi PS, Kronke M, Mak TW: Mice deficient for the 55Kd tumor necrosis factor receptor resistant to endotoxic shock, yet succumb to L-monocytogenes infection. Cell 73: 457–467, 1993
Zimmer A, Gruss P: Production of chimeric mice containing embryonic stem (ES) cells carrying a homeobox hox-1.1 allele mutated by homologous recombination. Nature 338: 150–153, 1989
Philpott KL, Viney JL, Kay G, Rastan S, Gardiner EM, Chae S, Hayday AC, Owen MJ: Lymphoid development in mice congenitally lacking T cell receptor αβ-expressing cells. Science 256: 1448–1452, 1992
Feldhaus A, Klug CA, Arvin KL, Singh H: Targeted disruption of the oct-2 locus in a B cell provides genetic eidence for two distinct cell type-specific pathways of octamer element mediated gene activation. EMBO J 12: 2763–2772, 1993
Kishihara K, Penninger J, Wallace VA, Kundig TM, Kawai K, Wakeham A, Timms E, Pfeffer K, Ohashi PS, Thomas ML, Furlonger C, Paige CJ, Mak TW: Normal β lymphocyte development but impaired T cell maturation in CD45-exon 6 protein tyrosine phosphatase-deficient mice. Cell 74: 143–156, 1993
Kitamura D, Rose J, Kuhn R, Rajewsky K: A B cell deficient mouse by targeted disruption of the membrane exon of the immunoglobulin μ chain gene. Nature 350: 423–426, 1991
McMahon AP, Bradley A: The Wnt-1 (int-1) protooncogene is required for development of a large region of the mouse brain. Cell 62: 1073–1085, 1990
Thomas KR, Capecchi MR: Targeted disruption of the murine int-1 protooncogene resulting in severe abnormalities in midbrain and cerebellar development. Nature 346: 847–850, 1990
Pevny I, Simon MC, Robertson E, Klein WH, Tsai S-F, D'agati V, Orkin SH, Costantini F: Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature 349: 257–260, 1991
Dechiara TM, Efstratiadis A, Robertson EJ: A growth deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupte by targeting. Nature 345: 78–80, 1990
Steeg GM, Ellis J, Bernstein A: Introduction of specific point mutations into RNA polymerase II by gene targeting in mouse embryoni stem cells. Evidence for a DNA mis-match repair mechanism. Proc Natl Acad Sci USA 87: 4680–4684, 1990
Shahinian A, Pfeffer K, Lee KP, Kundig TM, Kishihara K, Wakeham A, Kawai K, Ohashi PS, Thompson CB, Mak TW: Differential T cell costimulatory requirements in CD28-deficient mice. Science 261: 609–612, 1993
Lee EY-H, Chang CY, Hu N, Wang Y-CJ, Lai CC, Herrup K, Lee W-H Bardley A: Mice deficient for RB are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359: 288–294, 1992
Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA: Effects of an RB mutation in the mouse. Nature 359: 295–300, 1992
Clarke AR, Maandag ER, Van Roon M, Van der Lugt NMT, Van der, Valk M, Hooper ML, Berns A te Riele H: Requirement for a functional RB-1 gene in murine development. Nature 359: 328–330, 1992
Hasty P, Bradley A, Morris JH, Edmondson DG, Venuti JM, Olson EN, Klein WH: Muscle deficiency and neonatal death in mice with targeted mutation in the myogenin gene. Nature 364: 501–506, 1993
Nabeshima Y, Hanaoka K, Hayasaka M, Esumi E, Shaowei Li, Nonaka I Nabeshima YI: Myogenin gene disruption results in perinatal lethality because of sever muscle defect. Nature 364: 532–535, 1993
Lufkin T, Lohnes D, Mark M, Dierich A, Gorry P, Gaub M-P, LeMeur M, Chambon P: High postnatal lethality an testis degeneration in retinoic acid receptor α mutant mice. Proc Nat Acad Sci USA 90: 7225–7229, 1993
Love PE, Shores EW, Johnson MD, Tremblay ML, Lee EJ, Grinberg A, Huang SP, Singer A, Westphal H: T cell development in mice that lack the zeta chain of the T cell antigen receptor complex. Science 261: 918–921, 1993
Mayadas TN, Johnson RC Rayburn H, Hynes RO, Wagner DD: Leukocyte rolling and extravasation are severely compromised in P seletin-deficient mice. Cell 74: 541–554, 1993
Ishibashi S, Brown MS, Goldstein JL, Gerard RD, Hammer RE, Herz J: Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest 92: 883–893, 1993
Kreidberg JA, Ariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R: WT-1 is required for early kidney development. Cell 74: 679–691, 1993
Deursen J, Heerschap A, Oerlemans F, Ruitenbeek W, Jap P, Laak H Wieringa Be: Skeletal muscles of mice deficient in muscle creatin kinase lack burst activity. Cell 74: 621–631, 1993
Rothe J, Lesslauer W, Lotscher H, Lang Y, Koebel P, Kontgen F, Althage A, Zinkernagel R, Steinmetz M, Bluethmann H: Mice lacking the tumor necrosis factor receptor 1 are resistant to TNF mediated toxicity but highly susceptible to infection byListeria monocytogenes. Nature 364: 798–802, 1993
Carpenter EM, Goddard JM, Chisaka O, Manley NR, Capecchi MR: Loss of Hox-A1 (Hox-1.6) function results in the reorganization of the murine hindbrain. Development 118: 1063–1075, 1993
Kopf M, Gros GL, Bachmann M, Lamers MC, Bluethmann H, Kohler G: Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature 362: 245–248, 1993
Mansour SL, Goddard JM, Capecchi M: Mice homozygous for a targeted disruption of the protooncogene int-2 have developmental defects in the tail and inner ear. Development 117: 13–28, 1993
Dalton DK, Pitts-Meek S, Keshav S, Figari IS, Bradley A, Stewart TA: Multiple defects of immune cell function in mice with disrupted interferon gamma gene. Science 259: 1739–1742, 1993
Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamigo R, Vilcek J, Zinkernagel RM, Arguet M: Immune response in mice that lack the interferon gamma receptor. Science 259: 1742–1745, 1993
Itohara S, Mombaerts P, Lafaille J, Sacomini J, Nelson A, Clarke AR, Hooper ML, Farr A, Tonegawa S: T cell receptor delta gene mutant mice: Independent generation of αβ T cells and programmed rearrangements of γ delta TCR genes. Cell 72: 337–348, 1993
Mombaerts P, Clarke AR, Rudnicki MA, Iacomini J, Itohara S, Lafaille JJ, Wang L, Ishikawa Y, Jaenisch R, Hooper ML, Tonegawa S: Mutation in T-cell antigen receptor genes α and β block thymocyte development at different stages. Nature 360: 225–231, 1992
Komori T, Okada A, Stewart V, Alt FW: Lack of N regions in antigen receptor variable region genes of TdT-deficient lymphocytes. Science 261: 1171–1174, 1993
Gilfillan S, Dierich A, Lemeur M, Benoist C, Mathis D. Mice lacking TdT: Mature animals with an immature lymphocyte repertoire. Science 261: 1175–1178, 1993
Koller BH, Marrack P, Kappler JW, Smithies O: Normal development of mice deficient in β-2 microglobulin, MHC class 1 proteins and CD8+ cells Science 248: 1227–1230, 1990
Wang ZQ, Ovitt C, Grigoriadis AE, Mohlesteinlein U, Ruther U Wagner EF: Bone and hematopoietic defects in mice lacking c-fos. Nature 360: 741–745, 1992
Homanics GE, Smith TJ, Zhang SH, Lee D, Young SG, Maeda N: Targeted modification of the apolipoprotein B gene results in hypolipoproteninemia and developmental abnormalities in mice. Proc Nat Acad Sci USA 90: 2389–2393, 1993
Farese RV Jr, Flynn LM, Young SG: Modication of the apolipoprotein B gene in Hep G2 cells by gene targeting. J Clin Invest 90: 256–261, 1992
Jakobovits D, Vergara GJ, Kennedy JL, Hales JF, McGuinness RP, Casentiniborocz ED, Breener DG, Otten GR: Analysis of homozygous mutant chimeric mice-Deletion of the immunolobulin heavy chain joining region blocks B cell development and antibody production. Proc Nat Acad Sci USA 90: 2551–2555, 1993
Zou, YR, Takeda S, Rajewsky K: Gene targeting in the immunoglobulin kappa locus. Efficient generation of lambda chain expressing B cells independent of gene rearrangements in the immunoglobulin kappa. EMBO J 12: 811–820, 1993
Cheng J, Trounstine M, Kurahara C, Young F, Kuo CC, Xu Y, Loring JF, Alt, FW, Huszar D: B cell development in mice that lack one or both immunoglobulin kappa light chain gene. EMBO J 12: 821–830, 1993
Nitschke L, Kosco MH, Kohler MC: Immunoglobulin D deficient mice can mount normal immune responses to thymus-independent and thymus-dependent antigens. Pro Nat Acad Sci USA 90: 1887–1891, 1993
Serwe M, Sablitzky: V(D)J recombination in B cells is impaired but not blocked by targeted deletion of the immunoglobulin heavy chain intron enhancer. EMBO J 12: 2321–2327, 1993
Takeda S, Zou YR, Bluethmann H, Kitamura D, Muller U, Rajewsky K: Deletion of the immunoglobulin kappa chain intron enhancer abolishes kapp-chain gene rearrangement in cis but not lambda chain gene rearrangement in trans. EMBO J 12: 2329–2336, 1993
Ehlich A, Schaal S, Gu H, Kitamura D, Muller W, Rajewsky K: Immunoglobulin heavy and light chain genes rearrange independently at early stages of B cell development. Cell 72: 695–704, 1993
Stanton BR, Perkins AS, Fessarollo L, Sassoon DA, Parada LF: Loss of N-myc function results in embryonic lethality and failure of the epithelial component of the embryo to develop. Genes Dev 6: 2235–2247, 1992
Davis AC, Wims M, Spotts GD, Hann SR, Bradley A: A null c-Myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice. Genes Dev 7: 671–682, 1993
Charron J, Malynn BA, Fisher P, Stewart V, Jeannotte L, Goff SP, Robertson EJ, Alt FW: Embryonic lethality in mice homozygous for a targeted disrutpion on the N-myc. Genes Dev 6: 2248–2257, 1992
Grusby MJ, Auchincloss H, Lee R, Johnson RS, Spencer JP, Zejlstra M, Jaenisch R, Papaioannou VE, Glimcher LH: Mice lacking major histocompatibility complex class I and class II molecules. Proc Nat Acad Sci USA 90: 3913–3917, 1993
Episkopou V, Maeda S, Nishiguchi S, Shimada K, Gaitanaris GA, Gottesman ME, Robertson EJ: Disruption of the transthyretin gene results in mice with depressed levels of plasma retinal and thyroid hormone. Proc Nat Acad Sci USA 90: 2375–2379, 1993
Dorin JR, Dickinson P, Alton EWFW, Smith SN, Geddes DM, Sterenson BJ, Kimber WL, Fleming S, Clarke AR, Hooper ML, Anderson L, Beddington RSP, Porteous DJ: Cystick fibrosis in the mouse by targeted insertional mutagenesis. Nature 359: 211–215, 1992
Michalska AE, Choo KHA: Targeting and germ line transmission of a null mutation at the metallothionein I and II loci in mouse. Proc Nat Acad Sci USA 90: 8088–8092, 1993
Masu Y, Wolf E, Holtmann B, Sendtner M, Brem G, Thoenen H: Disruption of the CNTF gene results in motor neuron degeneration. Nature 365: 27–32, 1993
Silva AJ, Stevens CF, Tonegawa S, Wang Y: Deficient hippocampal long term potentiation in α calcium-calmodulin kinase II mutant mice. Science 257: 201–206, 1992
Silva AJ, Paylor R, Wehner JM, Tonegawa S: Impaired spatial learning in α calcium-calmodulin kinase II mutant mice. Science 257: 206–211 1992
Tybulewicz VLJ, Tremblay ML, LaMarca ME, Willemsen R, Stubblefield BK, Winfield S, Zablocka B, Sidransky E, Martin BM, Huang SP, Mintzer KA, Westphal S, Mulligan RC, Ginnes EI: Animal model of Gaucher's disease from targeted disruption of the mouse gluococerebrosidase gene. Nature 357: 407–410, 1992
Kitamura D, Rajewsky K: Targeted disruption of μ chain membrane exon causes loss of heavy-chain allelic exclusion. Nature 356: 154–156, 1992
Kuhn R, Rajewsky K, Muller W: Generation and analysis of interleukin-4 deficient mice. Science 254: 707–710, 1991
Rahemtulla A, Fung-Leung WP, Schilham MW, Kundig TM, Sambhara SR, Narendran A, Arabian A, Wakeham A, Paige CJ, Zinkernagel RM, Miller RG, Mak TW: Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4. Nature 353: 180–184, 1991
Grunsby MJ, Johnson RS, Papaioannou VE, Glimcher LH. Depletion of CD4+ T cells in major histocompatibility complex Class II-deficient mice. Science 253, 1417–1420, 1991
Killeen S, Sawada S, Littman DR: Regulated expression of human CD4 rescues helper T cell development in mice lacking expression of endogenous CD4. EMBO J 12: 1547–1553, 1993
Fung-Leung, W-P, Schilham MW, Rahemtulla A, Kundig TM, Vollenwider M, Potter J, Van Ewijk W, Mak TW: CD8 is needed for development of cytotoxic T cells but not helper T cells. Cell 65: 443–449, 1991
Schorle H, Holtschke T, Hunig T, Schimpl A, Horak I: Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352: 621–624, 1991
Locksely RM, Reiner SL, Hatam F, Littman DR, Killeen N. Helper T cells without CD4: Control of Leishmaniasis in CD4 deficient mice. Science 261: 1448–1451, 1993
Hilberg F, Aguzzi A, Howells N, Wagner EF: c-Jun is essential for normal mouse development and hepatogenesis. Nature 365: 179–181, 1993
Love PE, Tremblay ML, Westphal H: Targeting of the T-cell receptor zeta chain gene in embryonic stem cells: Strategies for generating multiple mutations in a single gene. Proc Nat Acad Sci USA 89: 9929–9933, 1992
Moens CB, Auerback AB, Conlon RA, Joyner AL, Rossant J: A targeted mutation reveals a role for N-myc in branching morphogenesis in the embryonic mouse lung. Genes and Dev 6: 691–704, 1992
Killeen N, Stuart SG, Littman DR: Development and function of T cells in mice with a disrupted CD2 gene. EMBO J 11: 4329–4336, 1992
Sligh JE Jr, Ballantyne DM, Rich SS, Hawkings HK, Smith CW, Bradley A Beaudet AL: Inflammatory and immune responses are impaired in mice deficient in intracellular adhesion molecule 1. Proc Nat Acad Sci. USA 90: 8529–8533, 1993
Nakayama IK, Nakayama K, Negishi I, Kuida K, Shinkai Y, Louie MC, Fields LE, Lucas PJ, Stewart V, Alt FW, Loh DY: Disappearance of the lymphoid system in Bc 1-2 homozygous mutant chimeric mice. Science 261: 1584–1588, 1993
Liu JP, Baker J, Perkins AS, Roberton EJ, Efstratiadis A: Mice carrying null mutations of the genes encoding insulin-like growth factor-1 (lgf-1) and type 1 IGF receptor (Igflr). Cell 75: 59–72, 1993
Matsuyama T, Kimura T, Kitagawa M, Pfeffer K, Kawakami T, Watanabe N, Kundig TM, Amakawa R, Kishihara K, Wakeham, Potter J, Furlonger CL, Narendran A, Suzuki H, Ohashi PS, Paige CJ, Taniguchi T, Mak TW: Targeted disruption of IRF-1 or IRF-2 results in abnormal type 1 IFN gene induction and aberrant lymphocyte development. Cell 75: 83–97, 1993
Klein R, Smeyne RJ, Wurst W, Long LK, Auerback BA, Joyner AL, Barbacid M: Targeted disruption of the trkB neurotrophin recepton gene results in nervous system lesions and neonatal death. Cell 75: 113–122, 1993
Steinmetz M, Haas W. Recent experiments with MHC knock-out mice: More questions than aswers. BioEssays 15: 613–615, 1993
Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ: Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys and hypopigmented hair. Cell 75: 229–240, 1993
Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W: Intereukin-10-deficient mice develop chronic enterocolitis. Cell 75: 263–274, 1993
Moens, CB, Stanton BR, Parada LF, Rossant J: Defects in heart and lung development in compound heterzygotes for two different targeted mutations at the N-myc locus. Development 119: 485–499, 1993
Ohno H, Aoe T, Taki S, Kitamura D, Ishida Y, Rajewsky K, Saito T: Developmental and functional impairment of T cells in mice lacking CD3 zeta chains. EMBO J 12: 4357–4366, 1993
Malissen M, Gillet A, Rocha B, Trucy J, Vivier E, Boyer C, Kontgen F, Frun N, Mazza G, Spanopoulou E, Guy-Grand D, Malissen B: T cell development in mice lacking the CD3-Zeta/Eta gene. EMBO J 12: 4347–4355, 1993
Dolle P, Dierich A, LeMeur M, Schimmang T, Schuhbaur B, Chambon P, Duboule D: Disruption of the hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs. Cell 75: 431–441, 1993
Smit JJM, Schinkel AH, Oude Elferink RPJ, Groen AK, Wagenaar E, Van Deemter L, Mol CAAM, Ottenhoff R, Van der Lugt NMT, Van Roon MA, Van der Valk MA, Offerhaus GJA, Berns AJM, Borst P: Homozygous disruption of the murine mdr 2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75: 451–462, 1993
Guillemot F, Li-Ching Lo, Johnson JE, Auerbak A, Anderson DJ, Joyner AL: Mammailian achaete-scute homolog 1 is required for the early development of ol factory and autonomic neurons. Cell 75: 463–476, 1993
Chih-Pin Liu; Ueda R, Shi J, Sancho J, Wang B, Weddell G, Loring J, Kurahara C, Dudley EC, Hayday A, Terhorst C, Huang M: Abnormal T cell development in CD-3 Zeta mutant mice and identification of a novel T cell population in the intestine. EMBO J 12: 4863–4875, 1993
Freeman GJ, Borriello F, Hodes RJ, Reiser H, Hathcock KH, Laszlo G, McKnight AJ, Kim J, Du L, Lombard DB, Gray GS, Nadler LM, Sharpe AH: Uncovering of functional alternative CTLA-4 counter-receptor in B7 deficient mice. Science 262: 907–909, 1993
Rosahl TW, Geppert M, Spillane D, Herz J, Hammer RE, Malenka RC, Sudhof TC: Short term synaptic plasticity is altered in mice lacking synapsin 1. Cell 75: 661–670, 1993
Condie BG, Capecchi MR: Mice homozygous for a targeted disruption of hoxd-3 (Hox-4.1) exhibit anterior transformations of the first and second cervical vertebrae, the atlas and the axis. Development 119: 579–595, 1993
Swiatek PJ, Gridley T: Perinatal lethality and defects in hind brain development in mice homozygous for a targeted mutation of the zinc finger gene Krox 20. Genes Dev 7: 2071–2084, 1993
Dombrowicz D, Flamand V, Brigman KK, Koller BH, Kinet JP: Abolition of anaphylaxis by targeted disruption of the high affinity immunoglobulin E receptor alpha chain gene. Cell 75: 969–976, 1993
Schneider-Maunoury S, Topilko P, Seitanidou T, Levi G, Cohen-Tannoudji M, Pournin S, Babinet C, Charnay P: Disruption of krox-20 results in alteration of rhombomeres 3 and 5 in the developing hindbrain. Cell 75: 1199–1214, 1993
Ludwig T, Ovitt CE, Beuer U, Hollinshed M, Remmler J, Lobel P, Ruther U, Hoflack B: Targeted disruption of the mouse cation-dependent mannose 6-phosphate receptor results in partial missorting of multiple lysosomal enzymes. EMBO J 12: 5225–5235, 1993
Koster A, Saftig P, Matzner U, von Figura K, Peters C, Pohlmann R: Targeted disruption of the Mr 46000 mannose 6-phosphate receptor gene im mice results in misrouting of lysosomal proteins EMBO J 12: 5219–5224, 1993
Yagi T, Aizawa S, Tokunaga T, Shigetani, Takeda N, Ikawa Y: A role for fyn tyrosine kinase in the sucking behaviour of neonatal mice. Nature 366: 742–745, 1993.
Poirier F, Robertson EJ: Normal development of mice carrying a null mutation in the gene encoding the L14S-type lectin. Development 119: 1229–1236, 1993
Abeliovich A, Chen C, Goda Y, Silva AJ, Stevens CF, Tonegawa S: Modified hippocampal long-term potentiation in PKCγ-mutant mice. Cell 75: 1253–1262, 1993
Abeliovich A, Paylor R, Chen C, Kim JJ, Wehner JM, Tonegawa S: PKCγ mutant mice exhibit mild deficits in spatial and contextual learning. Cell 75: 1263–1271, 1993
Huang PL, Dawson TM, Bredt DS, Snyder SH Fishman MC: Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75: 1273–1286, 1993
Gendron-Mauire M, Mallo M, Zhang M, Gridley T: Hoxa-2 mutant mice exhibit homeotic transformation of skeletal elements derived from cranial neural crest. Cell 75: 1317–1331, 1993.
Rijli FM, Mark M, Lakkaraju S, Dierich A, Dolle P, Chambon P: A homeotic transformation is generated in the rostral branchial region of the head by disruption of the hoxa-2, which acts as a selector gene. Cell 75: 1333–1349, 1993
Rudnicki MA, Schnegelsber PNJ, Stead RM, Braun T, Arnold HH, Jaenisch R: Myo D or Myf-5 is required for the formation of the skeletal muscle. Cell 75: 1351–1359, 1993
Carmeliet P, Kieckens L, Schoonjans L, Ream B, Van Nuffelen A, Prendergast G, Cole M, Bronson R, Collen D, Mulligan RC: Plasminogen activator inhibitor-1 gene-deficient mice. J Clin Invest 92: 2746–2755, 1993
Carmeliet P, Stassen JM, Schoonjans L, Ream B, Van den Oord JJ, De Mo M, Mulligan RC Collen D: Plasminogen activator inhibitor-1-gene-deficient mice. J Clin Invest 92: 2756–2760, 1993
Mcwhir J, Selfridge J, Harrison DJ, Squires S, Melton DW: Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning. Nature Genet 5: 217–224, 1993
Schuchardt A, D'Agati V, Larsson-Blomberg L, Costantini F, Pachnis V: Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor ret. Nature 367: 380–383, 1994
Masters BA, Kelly EJ, Quaife CJ, Brinster RL, Palmiter RD: Targeted disruption of metallothionein I and II genes increases sensitivity to cadmium. Proc Nat Acad Sci USA 91: 584–588, 1994
Ioffe E, Stanley P: Mice lacking N-acetylglucosaminyltransferase I activity die at mid-gestation, revealing an essential role for complex or hybrid N-linked carbohydrates. Proc Nat Acad Sci USA 91: 728–732, 1994
Wu X, Wakamiya M, Vaishnav S, Geske R, Montgomery Jr C, Jones P, Bradley A, Caskey CT: Hyperuricemia and urate nephropathy in urate oxidase deficient mice. Proc Nat Acad Sci USA 91: 742–746, 1994
Cremer H, Lange R, Christoph A, Plomann M, Vopper G, Roes J Brown R, Baldwin S, Kraemer P, Scheff S, Barthels D, Rajewsky K, Wille W: Inactivation of the N-CAM gene in mice results in size reduction of the olfactory bulb and deficits in spatial learning. Nature 367: 455–459, 1994
Li, Y, Erzurumlu RS, Chen C, Jhaveri S, Tonegawa S: Whisker-related neuronal patterns fails to develop in the trigeminal brainstem nuclei of NMDAR1 knockout mice. Cell 76: 427–437, 1994
Takai T, Li M, Sylvestre D, Clynes R, Ravetch JV: FcRγ chain deletion results in pleiotrophic effector cell defects. Cell 76: 519–529, 1994
Nakayama KI, Nakayama K, Negishi I, Kuida K, Louie MC, Kanagawa O, Nakauchi H, Loh DY: Requirement for CD8β chain in positive selection of CD8-lineage T cells. Science 263: 1131–1133, 1994
Koyasu S, Hussey RE, Clayton LK, Lerner A, Pedersen R, Delany-Heiken P, Chau F, Reinherz EL: Targeted disruption within the CD3 zeta/Eta/ϑ/Oct-1 locus in mouse. EMBO J 13: 784–797, 1994
Cosgrove D, Gray D, Dierich A, Kaufman J, Lemeur M, Benoist C, Mathis D: Mice lacking MHC Class II molecules. Cell 66: 1051–1066, 1991
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Shastry, B.S. More to learn from gene knockouts. Mol Cell Biochem 136, 171–182 (1994). https://doi.org/10.1007/BF00926078
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00926078