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Modeling human neurodegenerative diseases in transgenic systems

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Abstract

Transgenic systems are widely used to study the cellular and molecular basis of human neurodegenerative diseases. A wide variety of model organisms have been utilized, including bacteria (Escherichia coli), plants (Arabidopsis thaliana), nematodes (Caenorhabditis elegans), arthropods (Drosophila melanogaster), fish (zebrafish, Danio rerio), rodents (mouse, Mus musculus and rat, Rattus norvegicus) as well as non-human primates (rhesus monkey, Macaca mulatta). These transgenic systems have enormous value for understanding the pathophysiological basis of these disorders and have, in some cases, been instrumental in the development of therapeutic approaches to treat these conditions. In this review, we discuss the most commonly used model organisms and the methodologies available for the preparation of transgenic organisms. Moreover, we provide selected examples of the use of these technologies for the preparation of transgenic animal models of neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) and Parkinson’s disease (PD) and discuss the application of these technologies to AD as an example of how transgenic modeling has affected the study of human neurodegenerative diseases.

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References

  • Abbott A (2004) Laboratory animals: the Renaissance rat. Nature 428:464–466

    Article  PubMed  CAS  Google Scholar 

  • Agca C, Fritz JJ, Walker LC, Levey AI, Chan AW, Lah JJ, Agca Y (2008) Development of transgenic rats producing human beta-amyloid precursor protein as a model for Alzheimer’s disease: transgene and endogenous APP genes are regulated tissue-specifically. BMC Neurosci 9:28

    Article  PubMed  CAS  Google Scholar 

  • Albanese C, Hulit J, Sakamaki T, Pestell RG (2002) Recent advances in inducible expression in transgenic mice. Semin Cell Dev Biol 13:129–141

    Article  PubMed  CAS  Google Scholar 

  • Amacher SL (2008) Emerging gene knockout technology in zebrafish: zinc-finger nucleases. Brief Funct Genomic Proteomic 7:460–464

    Article  PubMed  CAS  Google Scholar 

  • Amsterdam A, Nissen RM, Sun Z, Swindell EC, Farrington S, Hopkins N (2004) Identification of 315 genes essential for early zebrafish development. Proc Natl Acad Sci USA 101:12792–12797

    Article  PubMed  CAS  Google Scholar 

  • An W, Han JS, Wheelan SJ, Davis ES, Coombes CE, Ye P, Triplett C, Boeke JD (2006) Active retrotransposition by a synthetic L1 element in mice. Proc Natl Acad Sci USA 103:18662–18667

    Article  PubMed  CAS  Google Scholar 

  • Anastassiadis K, Fu J, Patsch C, Hu S, Weidlich S, Duerschke K, Buchholz F, Edenhofer F, Stewart AF (2009) Dre recombinase, like Cre, is a highly efficient site-specific recombinase in E. coli, mammalian cells and mice. Dis Model Mech 2:508–515

    Article  PubMed  CAS  Google Scholar 

  • Arguello PA, Gogos JA (2010) Cognition in mouse models of schizophrenia susceptibility genes. Schizophr Bull 36:289–300

    Article  PubMed  Google Scholar 

  • Asakawa K, Suster ML, Mizusawa K, Nagayoshi S, Kotani T, Urasaki A, Kishimoto Y, Hibi M, Kawakami K (2008) Genetic dissection of neural circuits by Tol2 transposon-mediated Gal4 gene and enhancer trapping in zebrafish. Proc Natl Acad Sci USA 105:1255–1260

    Article  PubMed  CAS  Google Scholar 

  • Ash PE, Zhang YJ, Roberts CM, Saldi T, Hutter H, Buratti E, Petrucelli L, Link CD (2010) Neurotoxic effects of TDP-43 overexpression in C. elegans. Hum Mol Genet 19:3206–3218

    Article  PubMed  CAS  Google Scholar 

  • Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295:865–868

    Article  PubMed  CAS  Google Scholar 

  • Bai Q, Garver JA, Hukriede NA, Burton EA (2007) Generation of a transgenic zebrafish model of tauopathy using a novel promoter element derived from the zebrafish eno2 gene. Nucleic Acids Res 35:6501–6516

    Article  PubMed  CAS  Google Scholar 

  • Bateman JR, Lee AM, Wu CT (2006) Site-specific transformation of Drosophila via phiC31 integrase-mediated cassette exchange. Genetics 173:769–777

    Article  PubMed  CAS  Google Scholar 

  • Beaudet L, Cote F, Houle D, Julien JP (1993) Different posttranscriptional controls for the human neurofilament light and heavy genes in transgenic mice. Brain Res Mol Brain Res 18:23–31

    Article  PubMed  CAS  Google Scholar 

  • Bedford L, Hay D, Devoy A, Paine S, Powe DG, Seth R, Gray T, Topham I, Fone K, Rezvani N, Mee M, Soane T, Layfield R, Sheppard PW, Ebendal T, Usoskin D, Lowe J, Mayer RJ (2008) Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J Neurosci 28:8189–8198

    Article  PubMed  CAS  Google Scholar 

  • Bertram L, Tanzi RE (2004a) Alzheimer’s disease: one disorder, too many genes? Hum Mol Genet 13 Spec No 1:R135–41

    Google Scholar 

  • Bertram L, Tanzi RE (2004b) The current status of Alzheimer’s disease genetics: what do we tell the patients? Pharmacol Res 50:385–396

    Article  PubMed  CAS  Google Scholar 

  • Best BP (2009) Nuclear DNA damage as a direct cause of aging. Rejuvenation Res 12:199–208

    Article  PubMed  CAS  Google Scholar 

  • Beumer K, Bhattacharyya G, Bibikova M, Trautman JK, Carroll D (2006) Efficient gene targeting in Drosophila with zinc-finger nucleases. Genetics 172:2391–2403

    Article  PubMed  CAS  Google Scholar 

  • Beumer KJ, Trautman JK, Bozas A, Liu JL, Rutter J, Gall JG, Carroll D (2008) Efficient gene targeting in Drosophila by direct embryo injection with zinc-finger nucleases. Proc Natl Acad Sci USA 105:19821–19826

    Article  PubMed  CAS  Google Scholar 

  • Bezard E, Przedborski S (2011) A tale on animal models of Parkinson’s disease. Mov Disord 26:993–1002

    Article  PubMed  Google Scholar 

  • Bill BR, Petzold AM, Clark KJ, Schimmenti LA, Ekker SC (2009) A primer for morpholino use in zebrafish. Zebrafish 6:69–77

    Article  PubMed  CAS  Google Scholar 

  • Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005) Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45:675–688

    Article  PubMed  CAS  Google Scholar 

  • Bischof J, Basler K (2008) Recombinases and their use in gene activation, gene inactivation, and transgenesis. Methods Mol Biol 420:175–195

    Article  PubMed  CAS  Google Scholar 

  • Boch J, Bonas U (2010) Xanthomonas AvrBs3 family-type III effectors: discovery and function. Annu Rev Phytopathol 48:419–436

    Article  PubMed  CAS  Google Scholar 

  • Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, Lahaye T, Nickstadt A, Bonas U (2009) Breaking the code of DNA binding specificity of TAL-type III effectors. Science 326:1509–1512

    Article  PubMed  CAS  Google Scholar 

  • Bonini NM, Fortini ME (2003) Human neurodegenerative disease modeling using Drosophila. Annu Rev Neurosci 26:627–656

    Article  PubMed  CAS  Google Scholar 

  • Borchelt DR, Davis J, Fischer M, Lee MK, Slunt HH, Ratovitsky T, Regard J, Copeland NG, Jenkins NA, Sisodia SS, Price DL (1996) A vector for expressing foreign genes in the brains and hearts of transgenic mice. Genet Anal 13:159–163

    Article  PubMed  CAS  Google Scholar 

  • Bosze Z, Hiripi L, Carnwath JW, Niemann H (2003) The transgenic rabbit as model for human diseases and as a source of biologically active recombinant proteins. Transgenic Res 12:541–553

    Article  PubMed  CAS  Google Scholar 

  • Brault V, Besson V, Magnol L, Duchon A, Herault Y (2007) Cre/loxP-mediated chromosome engineering of the mouse genome. Handb Exp Pharmacol 178:29–48

    Article  PubMed  CAS  Google Scholar 

  • Brenner M, Kisseberth WC, Su Y, Besnard F, Messing A (1994) GFAP promoter directs astrocyte-specific expression in transgenic mice. J Neurosci 14:1030–1037

    PubMed  CAS  Google Scholar 

  • Buchholz F, Angrand PO, Stewart AF (1998) Improved properties of FLP recombinase evolved by cycling mutagenesis. Nat Biotechnol 16:657–662

    Article  PubMed  CAS  Google Scholar 

  • Bugos O, Bhide M, Zilka N (2009) Beyond the rat models of human neurodegenerative disorders. Cell Mol Neurobiol 29:859–869

    Article  PubMed  Google Scholar 

  • Calhoun ME, Burgermeister P, Phinney AL, Stalder M, Tolnay M, Wiederhold KH, Abramowski D, Sturchler-Pierrat C, Sommer B, Staufenbiel M, Jucker M (1999) Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci USA 96:14088–14093

    Article  PubMed  CAS  Google Scholar 

  • Campbell WA, Yang H, Zetterberg H, Baulac S, Sears JA, Liu T, Wong ST, Zhong TP, Xia W (2006) Zebrafish lacking Alzheimer presenilin enhancer 2 (Pen-2) demonstrate excessive p53-dependent apoptosis and neuronal loss. J Neurochem 96:1423–1440

    Article  PubMed  CAS  Google Scholar 

  • Carbery ID, Ji D, Harrington A, Brown V, Weinstein EJ, Liaw L, Cui X (2010) Targeted genome modification in mice using zinc-finger nucleases. Genetics 186:451–459

    Article  PubMed  CAS  Google Scholar 

  • Carlson CM, Largaespada DA (2005) Insertional mutagenesis in mice: new perspectives and tools. Nat Rev Genet 6:568–580

    Article  PubMed  CAS  Google Scholar 

  • Carmine-Simmen K, Proctor T, Tschape J, Poeck B, Triphan T, Strauss R, Kretzschmar D (2009) Neurotoxic effects induced by the Drosophila amyloid-beta peptide suggest a conserved toxic function. Neurobiol Dis 33:274–281

    Article  PubMed  CAS  Google Scholar 

  • Carter RJ, Lione LA, Humby T, Mangiarini L, Mahal A, Bates GP, Dunnett SB, Morton AJ (1999) Characterization of progressive motor deficits in mice transgenic for the human Huntington’s disease mutation. J Neurosci 19:3248–3257

    PubMed  CAS  Google Scholar 

  • Casas C, Sergeant N, Itier JM, Blanchard V, Wirths O, van der Kolk N, Vingtdeux V, van de Steeg E, Ret G, Canton T, Drobecq H, Clark A, Bonici B, Delacourte A, Benavides J, Schmitz C, Tremp G, Bayer TA, Benoit P, Pradier L (2004) Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol 165:1289–1300

    Article  PubMed  CAS  Google Scholar 

  • Changeux JP (2010) Nicotine addiction and nicotinic receptors: lessons from genetically modified mice. Nat Rev Neurosci 11:389–401

    Article  PubMed  CAS  Google Scholar 

  • Cheah SS, Behringer RR (2001) Contemporary gene targeting strategies for the novice. Mol Biotechnol 19:297–304

    Article  PubMed  CAS  Google Scholar 

  • Cheng RK, Jesuthasan S, Penney TB (2011) Time for zebrafish. Front Integr Neurosci 5:40

    Article  PubMed  Google Scholar 

  • Chew SK, Rad R, Futreal PA, Bradley A, Liu P (2011) Genetic screens using the piggyBac transposon. Methods 53:366–371

    Article  PubMed  CAS  Google Scholar 

  • Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, Strome R, Zuker N, Loukides J, French J, Turner S, Lozza G, Grilli M, Kunicki S, Morissette C, Paquette J, Gervais F, Bergeron C, Fraser PE, Carlson GA, George-Hyslop PS, Westaway D (2001) Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem 276:21562–21570

    Article  PubMed  CAS  Google Scholar 

  • Choo BG, Kondrichin I, Parinov S, Emelyanov A, Go W, Toh WC, Korzh V (2006) Zebrafish transgenic Enhancer TRAP line database (ZETRAP). BMC Dev Biol 6:5

    Article  PubMed  CAS  Google Scholar 

  • Christian M, Cermak T, Doyle EL, Schmidt C, Zhang F, Hummel A, Bogdanove AJ, Voytas DF (2010) Targeting DNA double-strand breaks with TAL effector nucleases. Genetics 186:757–761

    Article  PubMed  CAS  Google Scholar 

  • Clarke J, Thornell A, Corbett D, Soininen H, Hiltunen M, Jolkkonen J (2007) Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats. Eur J Neurosci 26:1845–1852

    Article  PubMed  Google Scholar 

  • Crabtree DM, Zhang J (2011) Genetically engineered mouse models of Parkinson’s disease. Brain Res Bull. doi:10.1016/jbrainresbull.2011.07.019

  • Crews L, Rockenstein E, Masliah E (2010) APP transgenic modeling of Alzheimer’s disease: mechanisms of neurodegeneration and aberrant neurogenesis. Brain Struct Funct 214:111–126

    Article  PubMed  CAS  Google Scholar 

  • Cronin CA, Gluba W, Scrable H (2001) The lac operator-repressor system is functional in the mouse. Genes Dev 15:1506–1517

    Article  PubMed  CAS  Google Scholar 

  • Crowther DC, Kinghorn KJ, Miranda E, Page R, Curry JA, Duthie FA, Gubb DC, Lomas DA (2005) Intraneuronal Abeta, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer’s disease. Neuroscience 132:123–135

    Article  PubMed  CAS  Google Scholar 

  • Cui X, Ji D, Fisher DA, Wu Y, Briner DM, Weinstein EJ (2011) Targeted integration in rat and mouse embryos with zinc-finger nucleases. Nat Biotechnol 29:64–67

    Article  PubMed  CAS  Google Scholar 

  • Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90:537–548

    Article  PubMed  CAS  Google Scholar 

  • Davis MW, Morton JJ, Carroll D, Jorgensen EM (2008) Gene activation using FLP recombinase in C. elegans. PLoS Genet 4:e1000028

    Article  PubMed  CAS  Google Scholar 

  • De Gasperi R, Rocher AB, Sosa MA, Wearne SL, Perez GM, Friedrich VL Jr, Hof PR, Elder GA (2008) The IRG mouse: a two-color fluorescent reporter for assessing Cre-mediated recombination and imaging complex cellular relationships in situ. Genesis 46:308–317

    Article  PubMed  CAS  Google Scholar 

  • Deiters A, Yoder JA (2006) Conditional transgene and gene targeting methodologies in zebrafish. Zebrafish 3:415–429

    Article  PubMed  CAS  Google Scholar 

  • Deuschle U, Meyer WK, Thiesen HJ (1995) Tetracycline-reversible silencing of eukaryotic promoters. Mol Cell Biol 15:1907–1914

    PubMed  CAS  Google Scholar 

  • Distel M, Wullimann MF, Koster RW (2009) Optimized Gal4 genetics for permanent gene expression mapping in zebrafish. Proc Natl Acad Sci USA 106:13365–13370

    Article  PubMed  CAS  Google Scholar 

  • Dolphin CT, Hope IA (2006) Caenorhabditis elegans reporter fusion genes generated by seamless modification of large genomic DNA clones. Nucleic Acids Res 34:e72

    Article  PubMed  CAS  Google Scholar 

  • Dosanjh LE, Brown MK, Rao G, Link CD, Luo Y (2010) Behavioral phenotyping of a transgenic Caenorhabditis elegans expressing neuronal amyloid-beta. J Alzheimers Dis 19:681–690

    PubMed  CAS  Google Scholar 

  • Drake J, Link CD, Butterfield DA (2003) Oxidative stress precedes fibrillar deposition of Alzheimer’s disease amyloid beta-peptide (1–42) in a transgenic Caenorhabditis elegans model. Neurobiol Aging 24:415–420

    Article  PubMed  CAS  Google Scholar 

  • Draper BW, McCallum CM, Stout JL, Slade AJ, Moens CB (2004) A high-throughput method for identifying N-ethyl-N-nitrosourea (ENU)-induced point mutations in zebrafish. Methods Cell Biol 77:91–112

    Article  PubMed  CAS  Google Scholar 

  • Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383:710–713

    Article  PubMed  CAS  Google Scholar 

  • Duffy JB (2002) GAL4 system in Drosophila: a fly geneticist’s Swiss army knife. Genesis 34:1–15

    Article  PubMed  CAS  Google Scholar 

  • Dziennis S, Van Etten RA, Pahl HL, Morris DL, Rothstein TL, Blosch CM, Perlmutter RM, Tenen DG (1995) The CD11b promoter directs high-level expression of reporter genes in macrophages in transgenic mice. Blood 85:319–329

    PubMed  CAS  Google Scholar 

  • Echeverria V, Ducatenzeiler A, Alhonen L, Janne J, Grant SM, Wandosell F, Muro A, Baralle F, Li H, Duff K, Szyf M, Cuello AC (2004) Rat transgenic models with a phenotype of intracellular Abeta accumulation in hippocampus and cortex. J Alzheimers Dis 6:209–219

    PubMed  CAS  Google Scholar 

  • Ekker SC (2008) Zinc finger-based knockout punches for zebrafish genes. Zebrafish 5:121–123

    Article  PubMed  CAS  Google Scholar 

  • Elder GA, Friedrich VL Jr, Liang Z, Li X, Lazzarini RA (1994) Enhancer trapping by a human mid-sized neurofilament transgene reveals unexpected patterns of neuronal enhancer activity. Brain Res Mol Brain Res 26:177–188

    Article  PubMed  CAS  Google Scholar 

  • Elder GA, Gama Sosa MA, De Gasperi R (2010a) Transgenic mouse models of Alzheimer’s disease. Mt Sinai J Med 77:69–81

    Article  PubMed  Google Scholar 

  • Elder GA, Gama Sosa MA, De Gasperi R, Dickstein DL, Hof PR (2010b) Presenilin transgenic mice as models of Alzheimer’s disease. Brain Struct Funct 214:127–143

    Article  PubMed  CAS  Google Scholar 

  • Elia AJ, Parkes TL, Kirby K, St George-Hyslop P, Boulianne GL, Phillips JP, Hilliker AJ (1999) Expression of human FALS SOD in motorneurons of Drosophila. Free Radic Biol Med 26:1332–1338

    Article  PubMed  CAS  Google Scholar 

  • Emelyanov A, Parinov S (2008) Mifepristone-inducible LexPR system to drive and control gene expression in transgenic zebrafish. Dev Biol 320:113–121

    Article  PubMed  CAS  Google Scholar 

  • Emelyanov A, Gao Y, Naqvi NI, Parinov S (2006) Trans-kingdom transposition of the maize dissociation element. Genetics 174:1095–1104

    Article  PubMed  CAS  Google Scholar 

  • Etchberger JF, Hobert O (2008) Vector-free DNA constructs improve transgene expression in C. elegans. Nat Methods 5:3

    Article  PubMed  CAS  Google Scholar 

  • Ewald CY, Li C (2010) Understanding the molecular basis of Alzheimer’s disease using a Caenorhabditis elegans model system. Brain Struct Funct 214:263–283

    Article  PubMed  CAS  Google Scholar 

  • Faber PW, Alter JR, MacDonald ME, Hart AC (1999) Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc Natl Acad Sci USA 96:179–184

    Article  PubMed  CAS  Google Scholar 

  • Feany MB, Bender WW (2000) A Drosophila model of Parkinson’s disease. Nature 404:394–398

    Article  PubMed  CAS  Google Scholar 

  • Ferrari R, Kapogiannis D, Huey ED, Momeni P (2011) FTD and ALS: a tale of two diseases. Curr Alzheimer Res 8:273–294

    Article  PubMed  CAS  Google Scholar 

  • Finelli A, Kelkar A, Song HJ, Yang H, Konsolaki M (2004) A model for studying Alzheimer’s Abeta42-induced toxicity in Drosophila melanogaster. Mol Cell Neurosci 26:365–375

    Article  PubMed  CAS  Google Scholar 

  • Finkbeiner S (2011) Huntington’s disease. Cold Spring Harb Perspect Biol 3. doi:10.1101/cshperspect.a007476

  • Flood DG, Lin YG, Lang DM, Trusko SP, Hirsch JD, Savage MJ, Scott RW, Howland DS (2009) A transgenic rat model of Alzheimer’s disease with extracellular Abeta deposition. Neurobiol Aging 30:1078–1090

    Article  PubMed  CAS  Google Scholar 

  • Folkesson R, Malkiewicz K, Kloskowska E, Nilsson T, Popova E, Bogdanovic N, Ganten U, Ganten D, Bader M, Winblad B, Benedikz E (2007) A transgenic rat expressing human APP with the Swedish Alzheimer’s disease mutation. Biochem Biophys Res Commun 358:777–782

    Article  PubMed  CAS  Google Scholar 

  • Gaiano N, Amsterdam A, Kawakami K, Allende M, Becker T, Hopkins N (1996) Insertional mutagenesis and rapid cloning of essential genes in zebrafish. Nature 383:829–832

    Article  PubMed  CAS  Google Scholar 

  • Gama Sosa MA, De Gasperi R, Elder GA (2010a) Animal transgenesis: an overview. Brain Struct Funct 214:91–109

    Article  PubMed  CAS  Google Scholar 

  • Gama Sosa MA, Gasperi RD, Rocher AB, Wang AC, Janssen WG, Flores T, Perez GM, Schmeidler J, Dickstein DL, Hof PR, Elder GA (2010b) Age-related vascular pathology in transgenic mice expressing presenilin 1-associated familial Alzheimer’s disease mutations. Am J Pathol 176:353–368

    Article  PubMed  CAS  Google Scholar 

  • Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F et al (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:523–527

    Article  PubMed  CAS  Google Scholar 

  • Gan BQ, Tang BL (2010) Sirt1′s beneficial roles in neurodegenerative diseases—a chaperonin containing TCP-1 (CCT) connection? Aging Cell 9:924–929

    Article  PubMed  CAS  Google Scholar 

  • Gao X, Zhang P (2007) Transgenic RNA interference in mice. Physiology (Bethesda) 22:161–166

    Article  CAS  Google Scholar 

  • Garcia EL, Mills AA (2002) Getting around lethality with inducible Cre-mediated excision. Semin Cell Dev Biol 13:151–158

    Article  PubMed  CAS  Google Scholar 

  • Garrity SJ, Sivanathan V, Dong J, Lindquist S, Hochschild A (2010) Conversion of a yeast prion protein to an infectious form in bacteria. Proc Natl Acad Sci USA 107:10596–10601

    Article  PubMed  CAS  Google Scholar 

  • Gaszner M, Felsenfeld G (2006) Insulators: exploiting transcriptional and epigenetic mechanisms. Nat Rev Genet 7:703–713

    Article  PubMed  CAS  Google Scholar 

  • Gendron TF, Petrucelli L (2011) Rodent models of TDP-43 proteinopathy: investigating the mechanisms of TDP-43-mediated neurodegeneration. J Mol Neurosci 45(3):486–499

    Google Scholar 

  • Gentry MS, Dowen RH 3rd, Worby CA, Mattoo S, Ecker JR, Dixon JE (2007) The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease. J Cell Biol 178:477–488

    Article  PubMed  CAS  Google Scholar 

  • Gentry MS, Dixon JE, Worby CA (2009) Lafora disease: insights into neurodegeneration from plant metabolism. Trends Biochem Sci 34:628–639

    Article  PubMed  CAS  Google Scholar 

  • Germain DP, Fan JQ (2009) Pharmacological chaperone therapy by active-site-specific chaperones in Fabry disease: in vitro and preclinical studies. Int J Clin Pharmacol Ther 47(Suppl 1):S111–S117

    PubMed  CAS  Google Scholar 

  • Geurts AM, Cost GJ, Freyvert Y, Zeitler B, Miller JC, Choi VM, Jenkins SS, Wood A, Cui X, Meng X, Vincent A, Lam S, Michalkiewicz M, Schilling R, Foeckler J, Kalloway S, Weiler H, Menoret S, Anegon I, Davis GD, Zhang L, Rebar EJ, Gregory PD, Urnov FD, Jacob HJ, Buelow R (2009) Knockout rats via embryo microinjection of zinc-finger nucleases. Science 325:433

    Article  PubMed  CAS  Google Scholar 

  • Giraldo P, Montoliu L (2001) Size matters: use of YACs, BACs and PACs in transgenic animals. Transgenic Res 10:83–103

    Article  PubMed  CAS  Google Scholar 

  • Giraldo P, Rival-Gervier S, Houdebine LM, Montoliu L (2003) The potential benefits of insulators on heterologous constructs in transgenic animals. Transgenic Res 12:751–755

    Article  PubMed  CAS  Google Scholar 

  • Goldberg AD, Banaszynski LA, Noh KM, Lewis PW, Elsaesser SJ, Stadler S, Dewell S, Law M, Guo X, Li X, Wen D, Chapgier A, DeKelver RC, Miller JC, Lee YL, Boydston EA, Holmes MC, Gregory PD, Greally JM, Rafii S, Yang C, Scambler PJ, Garrick D, Gibbons RJ, Higgs DR, Cristea IM, Urnov FD, Zheng D, Allis CD (2010) Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140:678–691

    Article  PubMed  CAS  Google Scholar 

  • Golling G, Amsterdam A, Sun Z, Antonelli M, Maldonado E, Chen W, Burgess S, Haldi M, Artzt K, Farrington S, Lin SY, Nissen RM, Hopkins N (2002) Insertional mutagenesis in zebrafish rapidly identifies genes essential for early vertebrate development. Nat Genet 31:135–140

    Article  PubMed  CAS  Google Scholar 

  • Gossen M, Bujard H (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 89:5547–5551

    Article  PubMed  CAS  Google Scholar 

  • Gotz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9:532–544

    Article  PubMed  CAS  Google Scholar 

  • Gowing G, Philips T, Van Wijmeersch B, Audet JN, Dewil M, Van Den Bosch L, Billiau AD, Robberecht W, Julien JP (2008) Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase. J Neurosci 28:10234–10244

    Article  PubMed  CAS  Google Scholar 

  • Graham LD (2002) Ecdysone-controlled expression of transgenes. Expert Opin Biol Ther 2:525–535

    Article  PubMed  CAS  Google Scholar 

  • Gray M, Shirasaki DI, Cepeda C, Andre VM, Wilburn B, Lu XH, Tao J, Yamazaki I, Li SH, Sun YE, Li XJ, Levine MS, Yang XW (2008) Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J Neurosci 28:6182–6195

    Article  PubMed  CAS  Google Scholar 

  • Greeve I, Kretzschmar D, Tschape JA, Beyn A, Brellinger C, Schweizer M, Nitsch RM, Reifegerste R (2004) Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila. J Neurosci 24:3899–3906

    Article  PubMed  CAS  Google Scholar 

  • Groth C, Nornes S, McCarty R, Tamme R, Lardelli M (2002) Identification of a second presenilin gene in zebrafish with similarity to the human Alzheimer’s disease gene presenilin2. Dev Genes Evol 212:486–490

    Article  PubMed  CAS  Google Scholar 

  • Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX et al (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264:1772–1775

    Article  PubMed  CAS  Google Scholar 

  • Halpern ME, Rhee J, Goll MG, Akitake CM, Parsons M, Leach SD (2008) Gal4/UAS transgenic tools and their application to zebrafish. Zebrafish 5:97–110

    Article  PubMed  CAS  Google Scholar 

  • Hans S, Kaslin J, Freudenreich D, Brand M (2009) Temporally-controlled site-specific recombination in zebrafish. PLoS One 4:e4640

    Article  PubMed  CAS  Google Scholar 

  • Hara K, Kuwayama H, Yaginuma T, Niimi T (2008) Establishment of a tetracycline-off system using a piggybac-based vector as a gene functional analysis tool for the temporal targeting of gene expression. J Insect Biotechnol Sericol 77:3_159–3_166

    Google Scholar 

  • Harrington AJ, Hamamichi S, Caldwell GA, Caldwell KA (2010) C. elegans as a model organism to investigate molecular pathways involved with Parkinson’s disease. Dev Dyn 239:1282–1295

    Article  PubMed  CAS  Google Scholar 

  • Harvey BK, Richie CT, Hoffer BJ, Airavaara M (2011) Transgenic animal models of neurodegeneration based on human genetic studies. J Neural Transm 118:27–45

    Article  PubMed  Google Scholar 

  • Haskins ME, Giger U, Patterson DF (2006) Animal models of lysosomal storage diseases: their development and clinical relevance. In: Mehta A, Beck M, Sunder-Plassmann G (eds) Fabry disease: perspectives from 5 years of FOS, chap 6. Oxford PharmaGenesis, Oxford

  • Hauschild J, Petersen B, Santiago Y, Queisser AL, Carnwath JW, Lucas-Hahn A, Zhang L, Meng X, Gregory PD, Schwinzer R, Cost GJ, Niemann H (2011) Efficient generation of a biallelic knockout in pigs using zinc-finger nucleases. Proc Natl Acad Sci USA 108:12013–12017

    Article  PubMed  CAS  Google Scholar 

  • Hayashi S, McMahon AP (2002) Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev Biol 244:305–318

    Article  PubMed  CAS  Google Scholar 

  • He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P (2010) Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease. Nature 467:95–98

    Article  PubMed  CAS  Google Scholar 

  • Heng MY, Detloff PJ, Wang PL, Tsien JZ, Albin RL (2009) In vivo evidence for NMDA receptor-mediated excitotoxicity in a murine genetic model of Huntington disease. J Neurosci 29:3200–3205

    Article  PubMed  CAS  Google Scholar 

  • Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, Danner S, Abramowski D, Sturchler-Pierrat C, Burki K, van Duinen SG, Maat-Schieman ML, Staufenbiel M, Mathews PM, Jucker M (2004) Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 7:954–960

    Article  PubMed  CAS  Google Scholar 

  • Hodgson JG, Agopyan N, Gutekunst CA, Leavitt BR, LePiane F, Singaraja R, Smith DJ, Bissada N, McCutcheon K, Nasir J, Jamot L, Li XJ, Stevens ME, Rosemond E, Roder JC, Phillips AG, Rubin EM, Hersch SM, Hayden MR (1999) A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23:181–192

    Article  PubMed  CAS  Google Scholar 

  • Horev G, Ellegood J, Lerch JP, Son YE, Muthuswamy L, Vogel H, Krieger AM, Buja A, Henkelman RM, Wigler M, Mills AA (2011) Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. Proc Natl Acad Sci USA 108(41):17076–17081

    Google Scholar 

  • Horn C, Handler AM (2005) Site-specific genomic targeting in Drosophila. Proc Natl Acad Sci USA 102:12483–12488

    Article  PubMed  CAS  Google Scholar 

  • Houdebine LM (2010) Design of expression cassettes for the generation of transgenic animals (including insulators). Methods Mol Biol 597:55–69

    Article  PubMed  CAS  Google Scholar 

  • Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102

    Article  PubMed  CAS  Google Scholar 

  • Huang G, Ashton C, Kumbhani DS, Ying QL (2011a) Genetic manipulations in the rat: progress and prospects. Curr Opin Nephrol Hypertens 20:391–399

    Article  PubMed  Google Scholar 

  • Huang P, Xiao A, Zhou M, Zhu Z, Lin S, Zhang B (2011b) Heritable gene targeting in zebrafish using customized TALENs. Nat Biotechnol 29:699–700

    Article  PubMed  CAS  Google Scholar 

  • Huang X, Nguyen AT, Li Z, Emelyanov A, Parinov S, Gong Z (2011c) One step forward: the use of transgenic zebrafish tumor model in drug screens. Birth Defects Res C Embryo Today 93:173–181

    Article  PubMed  CAS  Google Scholar 

  • Igaz LM, Kwong LK, Lee EB, Chen-Plotkin A, Swanson E, Unger T, Malunda J, Xu Y, Winton MJ, Trojanowski JQ, Lee VM (2011) Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest 121:726–738

    Article  PubMed  CAS  Google Scholar 

  • Iijima K, Liu HP, Chiang AS, Hearn SA, Konsolaki M, Zhong Y (2004) Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer’s disease. Proc Natl Acad Sci USA 101:6623–6628

    Article  PubMed  CAS  Google Scholar 

  • Iijima K, Chiang HC, Hearn SA, Hakker I, Gatt A, Shenton C, Granger L, Leung A, Iijima-Ando K, Zhong Y (2008) Abeta42 mutants with different aggregation profiles induce distinct pathologies in Drosophila. PLoS One 3:e1703

    Article  PubMed  CAS  Google Scholar 

  • Irizarry MC, McNamara M, Fedorchak K, Hsiao K, Hyman BT (1997a) APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol 56:965–973

    Article  PubMed  CAS  Google Scholar 

  • Irizarry MC, Soriano F, McNamara M, Page KJ, Schenk D, Games D, Hyman BT (1997b) Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci 17:7053–7059

    PubMed  CAS  Google Scholar 

  • Ivics Z, Hackett PB, Plasterk RH, Izsvak Z (1997) Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon from fish, and its transposition in human cells. Cell 91:501–510

    Article  PubMed  CAS  Google Scholar 

  • Ivics Z, Izsvak Z, Chapman KM, Hamra FK (2011) Sleeping Beauty transposon mutagenesis of the rat genome in spermatogonial stem cells. Methods 53:356–365

    Article  PubMed  CAS  Google Scholar 

  • Izsvak Z, Ivics Z (2005) Sleeping Beauty hits them all: transposon-mediated saturation mutagenesis in the mouse germline. Nat Methods 2:735–736

    Article  PubMed  CAS  Google Scholar 

  • Izsvak Z, Frohlich J, Grabundzija I, Shirley JR, Powell HM, Chapman KM, Ivics Z, Hamra FK (2010) Generating knockout rats by transposon mutagenesis in spermatogonial stem cells. Nat Methods 7:443–445

    Article  PubMed  CAS  Google Scholar 

  • Jaaro-Peled H (2009) Gene models of schizophrenia: DISC1 mouse models. Prog Brain Res 179:75–86

    Article  PubMed  CAS  Google Scholar 

  • Jackson GR, Salecker I, Dong X, Yao X, Arnheim N, Faber PW, MacDonald ME, Zipursky SL (1998) Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 21:633–642

    Article  PubMed  CAS  Google Scholar 

  • Jang CW, Behringer RR (2007) Transposon-mediated transgenesis in rats. CSH Protoc 2007: pdb prot4866

  • Jankowsky JL, Slunt HH, Gonzales V, Savonenko AV, Wen JC, Jenkins NA, Copeland NG, Younkin LH, Lester HA, Younkin SG, Borchelt DR (2005) Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease. PLoS Med 2:e355

    Article  PubMed  CAS  Google Scholar 

  • Jankowsky JL, Younkin LH, Gonzales V, Fadale DJ, Slunt HH, Lester HA, Younkin SG, Borchelt DR (2007) Rodent A beta modulates the solubility and distribution of amyloid deposits in transgenic mice. J Biol Chem 282:22707–22720

    Article  PubMed  CAS  Google Scholar 

  • Jeibmann A, Paulus W (2009) Drosophila melanogaster as a model organism of brain diseases. Int J Mol Sci 10:407–440

    Article  PubMed  CAS  Google Scholar 

  • Jones WD (2009) The expanding reach of the GAL4/UAS system into the behavioral neurobiology of Drosophila. BMB Rep 42:705–712

    Article  PubMed  CAS  Google Scholar 

  • Jorgensen EM, Mango SE (2002) The art and design of genetic screens: caenorhabditis elegans. Nat Rev Genet 3:356–369

    Article  PubMed  CAS  Google Scholar 

  • Joyner AL, Guillemot F (1994) Gene targeting and development of the nervous system. Curr Opin Neurobiol 4:37–42

    Article  PubMed  CAS  Google Scholar 

  • Justice MJ, Noveroske JK, Weber JS, Zheng B, Bradley A (1999) Mouse ENU mutagenesis. Hum Mol Genet 8:1955–1963

    Article  PubMed  CAS  Google Scholar 

  • Kabashi E, Lin L, Tradewell ML, Dion PA, Bercier V, Bourgouin P, Rochefort D, Bel Hadj S, Durham HD, Vande Velde C, Rouleau GA, Drapeau P (2010) Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo. Hum Mol Genet 19:671–683

    Article  PubMed  CAS  Google Scholar 

  • Kasuga K, Shimohata T, Nishimura A, Shiga A, Mizuguchi T, Tokunaga J, Ohno T, Miyashita A, Kuwano R, Matsumoto N, Onodera O, Nishizawa M, Ikeuchi T (2009) Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease. J Neurol Neurosurg Psychiatry 80:1050–1052

    Article  PubMed  CAS  Google Scholar 

  • Kato T, Kubota M, Kasahara T (2007) Animal models of bipolar disorder. Neurosci Biobehav Rev 31:832–842

    Article  PubMed  CAS  Google Scholar 

  • Kawakami K (2005) Transposon tools and methods in zebrafish. Dev Dyn 234:244–254

    Article  PubMed  CAS  Google Scholar 

  • Kawakami K, Koga A, Hori H, Shima A (1998) Excision of the tol2 transposable element of the medaka fish, Oryzias latipes, in zebrafish, Danio rerio. Gene 225:17–22

    Article  PubMed  CAS  Google Scholar 

  • Kawakami K, Shima A, Kawakami N (2000) Identification of a functional transposase of the Tol2 element, an Ac-like element from the Japanese medaka fish, and its transposition in the zebrafish germ lineage. Proc Natl Acad Sci USA 97:11403–11408

    Article  PubMed  CAS  Google Scholar 

  • Kelly A, Hurlstone AF (2011) The use of RNAi technologies for gene knockdown in zebrafish. Brief Funct Genomics 10:189–196

    Article  PubMed  CAS  Google Scholar 

  • Khandelwal A, Chandu D, Roe CM, Kopan R, Quatrano RS (2007) Moonlighting activity of presenilin in plants is independent of gamma-secretase and evolutionarily conserved. Proc Natl Acad Sci USA 104:13337–13342

    Article  PubMed  CAS  Google Scholar 

  • Khanna R, Soska R, Lun Y, Feng J, Frascella M, Young B, Brignol N, Pellegrino L, Sitaraman SA, Desnick RJ, Benjamin ER, Lockhart DJ, Valenzano KJ (2010) The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease. Mol Ther 18:23–33

    Article  PubMed  CAS  Google Scholar 

  • Khapre RV, Samsa WE, Kondratov RV (2010) Circadian regulation of cell cycle: molecular connections between aging and the circadian clock. Ann Med 42:404–415

    Article  PubMed  CAS  Google Scholar 

  • Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J 26:3169–3179

    Article  PubMed  CAS  Google Scholar 

  • Knopf F, Schnabel K, Haase C, Pfeifer K, Anastassiadis K, Weidinger G (2010) Dually inducible TetON systems for tissue-specific conditional gene expression in zebrafish. Proc Natl Acad Sci USA 107:19933–19938

    Article  PubMed  CAS  Google Scholar 

  • Kraemer BC, Zhang B, Leverenz JB, Thomas JH, Trojanowski JQ, Schellenberg GD (2003) Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy. Proc Natl Acad Sci USA 100:9980–9985

    Article  PubMed  CAS  Google Scholar 

  • Kragh PM, Nielsen AL, Li J, Du Y, Lin L, Schmidt M, Bogh IB, Holm IE, Jakobsen JE, Johansen MG, Purup S, Bolund L, Vajta G, Jorgensen AL (2009) Hemizygous minipigs produced by random gene insertion and handmade cloning express the Alzheimer’s disease-causing dominant mutation APPsw. Transgenic Res 18:545–558

    Article  PubMed  CAS  Google Scholar 

  • Kudo T, Loh DH, Truong D, Wu Y, Colwell CS (2011a) Circadian dysfunction in a mouse model of Parkinson’s disease. Exp Neurol 232:66–75

    Article  PubMed  Google Scholar 

  • Kudo T, Schroeder A, Loh DH, Kuljis D, Jordan MC, Roos KP, Colwell CS (2011b) Dysfunctions in circadian behavior and physiology in mouse models of Huntington’s disease. Exp Neurol 228:80–90

    Article  PubMed  CAS  Google Scholar 

  • Kuwahara T, Koyama A, Gengyo-Ando K, Masuda M, Kowa H, Tsunoda M, Mitani S, Iwatsubo T (2006) Familial Parkinson mutant alpha-synuclein causes dopamine neuron dysfunction in transgenic Caenorhabditis elegans. J Biol Chem 281:334–340

    Article  PubMed  CAS  Google Scholar 

  • Lakso M, Vartiainen S, Moilanen AM, Sirvio J, Thomas JH, Nass R, Blakely RD, Wong G (2003) Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human alpha-synuclein. J Neurochem 86:165–172

    Article  PubMed  CAS  Google Scholar 

  • Lamb BT, Sisodia SS, Lawler AM, Slunt HH, Kitt CA, Kearns WG, Pearson PL, Price DL, Gearhart JD (1993) Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice (corrected). Nat Genet 5:22–30

    Article  PubMed  CAS  Google Scholar 

  • Langenau DM, Feng H, Berghmans S, Kanki JP, Kutok JL, Look AT (2005) Cre/lox-regulated transgenic zebrafish model with conditional myc-induced T cell acute lymphoblastic leukemia. Proc Natl Acad Sci USA 102:6068–6073

    Article  PubMed  CAS  Google Scholar 

  • Largaespada DA (2009a) Transposon mutagenesis in mice. Methods Mol Biol 530:379–390

    Article  PubMed  CAS  Google Scholar 

  • Largaespada DA (2009b) Transposon-mediated mutagenesis of somatic cells in the mouse for cancer gene identification. Methods 49:282–286

    Article  PubMed  CAS  Google Scholar 

  • Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkins NA, Price DL (2002) Human alpha-synuclein-harboring familial Parkinson’s disease-linked Ala-53–Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 99:8968–8973

    Article  PubMed  CAS  Google Scholar 

  • Leon WC, Canneva F, Partridge V, Allard S, Ferretti MT, DeWilde A, Vercauteren F, Atifeh R, Ducatenzeiler A, Klein W, Szyf M, Alhonen L, Cuello AC (2010) A novel transgenic rat model with a full Alzheimer’s-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J Alzheimers Dis 20:113–126

    PubMed  CAS  Google Scholar 

  • Levine MS, Cepeda C, Hickey MA, Fleming SM, Chesselet MF (2004) Genetic mouse models of Huntington’s and Parkinson’s diseases: illuminating but imperfect. Trends Neurosci 27:691–697

    Article  PubMed  CAS  Google Scholar 

  • Lewandoski M (2001) Conditional control of gene expression in the mouse. Nat Rev Genet 2:743–755

    Article  PubMed  CAS  Google Scholar 

  • Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, Gwinn-Hardy K, Paul Murphy M, Baker M, Yu X, Duff K, Hardy J, Corral A, Lin WL, Yen SH, Dickson DW, Davies P, Hutton M (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402–405

    Article  PubMed  CAS  Google Scholar 

  • Li X, Patel JC, Wang J, Avshalumov MV, Nicholson C, Buxbaum JD, Elder GA, Rice ME, Yue Z (2010) Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson’s disease mutation G2019S. J Neurosci 30:1788–1797

    Article  PubMed  CAS  Google Scholar 

  • Li H, Haurigot V, Doyon Y, Li T, Wong SY, Bhagwat AS, Malani N, Anguela XM, Sharma R, Ivanciu L, Murphy SL, Finn JD, Khazi FR, Zhou S, Paschon DE, Rebar EJ, Bushman FD, Gregory PD, Holmes MC, High KA (2011a) In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature 475:217–221

    Article  PubMed  CAS  Google Scholar 

  • Li MA, Turner DJ, Ning Z, Yusa K, Liang Q, Eckert S, Rad L, Fitzgerald TW, Craig NL, Bradley A (2011b) Mobilization of giant piggyBac transposons in the mouse genome. Nucleic Acids Res. doi:10.1093/nar/gkr764

  • Liang J, Liu E, Yu Y, Kitajima S, Koike T, Jin Y, Morimoto M, Hatakeyama K, Asada Y, Watanabe T, Sasaguri Y, Watanabe S, Fan J (2006) Macrophage metalloelastase accelerates the progression of atherosclerosis in transgenic rabbits. Circulation 113:1993–2001

    Article  PubMed  CAS  Google Scholar 

  • Lieschke GJ, Currie PD (2007) Animal models of human disease: zebrafish swim into view. Nat Rev Genet 8:353–367

    Article  PubMed  CAS  Google Scholar 

  • Lin CH, Tallaksen-Greene S, Chien WM, Cearley JA, Jackson WS, Crouse AB, Ren S, Li XJ, Albin RL, Detloff PJ (2001) Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum Mol Genet 10:137–144

    Article  PubMed  CAS  Google Scholar 

  • Link CD (1995) Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci USA 92:9368–9372

    Article  PubMed  CAS  Google Scholar 

  • Link CD (2001) Transgenic invertebrate models of age-associated neurodegenerative diseases. Mech Ageing Dev 122:1639–1649

    Article  PubMed  CAS  Google Scholar 

  • Lione LA, Carter RJ, Hunt MJ, Bates GP, Morton AJ, Dunnett SB (1999) Selective discrimination learning impairments in mice expressing the human Huntington’s disease mutation. J Neurosci 19:10428–10437

    PubMed  CAS  Google Scholar 

  • Liu BH, Wang X, Ma YX, Wang S (2004) CMV enhancer/human PDGF-beta promoter for neuron-specific transgene expression. Gene Ther 11:52–60

    Article  PubMed  CAS  Google Scholar 

  • Liu K, Hipkens S, Yang T, Abraham R, Zhang W, Chopra N, Knollmann B, Magnuson MA, Roden DM (2006) Recombinase-mediated cassette exchange to rapidly and efficiently generate mice with human cardiac sodium channels. Genesis 44:556–564

    Article  PubMed  CAS  Google Scholar 

  • Liu L, Orozco IJ, Planel E, Wen Y, Bretteville A, Krishnamurthy P, Wang L, Herman M, Figueroa H, Yu WH, Arancio O, Duff K (2008a) A transgenic rat that develops Alzheimer’s disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment. Neurobiol Dis 31:46–57

    Article  PubMed  CAS  Google Scholar 

  • Liu X, Li Z, Emelyanov A, Parinov S, Gong Z (2008b) Generation of oocyte-specifically expressed cre transgenic zebrafish for female germline excision of loxP-flanked transgene. Dev Dyn 237:2955–2962

    Article  PubMed  CAS  Google Scholar 

  • Ljubuncic P, Reznick AZ (2009) The evolutionary theories of aging revisited–a mini-review. Gerontology 55:205–216

    Article  PubMed  CAS  Google Scholar 

  • Lu B, Vogel H (2009) Drosophila models of neurodegenerative diseases. Annu Rev Pathol 4:315–342

    Article  PubMed  CAS  Google Scholar 

  • Lu XH, Fleming SM, Meurers B, Ackerson LC, Mortazavi F, Lo V, Hernandez D, Sulzer D, Jackson GR, Maidment NT, Chesselet MF, Yang XW (2009) Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant alpha-synuclein. J Neurosci 29:1962–1976

    Article  PubMed  CAS  Google Scholar 

  • Lublin AL, Gandy S (2010) Amyloid-beta oligomers: possible roles as key neurotoxins in Alzheimer’s disease. Mt Sinai J Med 77:43–49

    Article  PubMed  Google Scholar 

  • Luthi A, Van der Putten H, Botteri FM, Mansuy IM, Meins M, Frey U, Sansig G, Portet C, Schmutz M, Schroder M, Nitsch C, Laurent JP, Monard D (1997) Endogenous serine protease inhibitor modulates epileptic activity and hippocampal long-term potentiation. J Neurosci 17:4688–4699

    PubMed  CAS  Google Scholar 

  • Ma Y, Hu H, Berrebi AS, Mathers PH, Agmon A (2006) Distinct subtypes of somatostatin-containing neocortical interneurons revealed in transgenic mice. J Neurosci 26:5069–5082

    Article  PubMed  CAS  Google Scholar 

  • Mallajosyula JK, Kaur D, Chinta SJ, Rajagopalan S, Rane A, Nicholls DG, Di Monte DA, Macarthur H, Andersen JK (2008) MAO-B elevation in mouse brain astrocytes results in Parkinson’s pathology. PLoS One 3:e1616

    Article  PubMed  CAS  Google Scholar 

  • Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506

    Article  PubMed  CAS  Google Scholar 

  • Mardis ER (2011) A decade’s perspective on DNA sequencing technology. Nature 470:198–203

    Article  PubMed  CAS  Google Scholar 

  • Metzger D, Clifford J, Chiba H, Chambon P (1995) Conditional site-specific recombination in mammalian cells using a ligand-dependent chimeric Cre recombinase. Proc Natl Acad Sci USA 92:6991–6995

    Article  PubMed  CAS  Google Scholar 

  • Meyer M, de Angelis MH, Wurst W, Kuhn R (2010) Gene targeting by homologous recombination in mouse zygotes mediated by zinc-finger nucleases. Proc Natl Acad Sci USA 107:15022–15026

    Article  PubMed  CAS  Google Scholar 

  • Miller RL (2011) Transgenic mice: beyond the knockout. Am J Physiol Renal Physiol 300:F291–F300

    Article  PubMed  CAS  Google Scholar 

  • Minois N, Sykacek P, Godsey B, Kreil DP (2010) RNA interference in ageing research—a mini-review. Gerontology 56:496–506

    Article  PubMed  CAS  Google Scholar 

  • Miura M, Tamura T, Mikoshiba K (1990) Cell-specific expression of the mouse glial fibrillary acidic protein gene: identification of the cis- and trans-acting promoter elements for astrocyte-specific expression. J Neurochem 55:1180–1188

    Article  PubMed  CAS  Google Scholar 

  • Moens CB, Donn TM, Wolf-Saxon ER, Ma TP (2008) Reverse genetics in zebrafish by TILLING. Brief Funct Genomic Proteomic 7:454–459

    Article  PubMed  CAS  Google Scholar 

  • Mohr S, Bakal C, Perrimon N (2010) Genomic screening with RNAi: results and challenges. Annu Rev Biochem 79:37–64

    Article  PubMed  CAS  Google Scholar 

  • Montoliu L, Schedl A, Kelsey G, Lichter P, Larin Z, Lehrach H, Schutz G (1993) Generation of transgenic mice with yeast artificial chromosomes. Cold Spring Harb Symp Quant Biol 58:55–62

    Article  PubMed  CAS  Google Scholar 

  • Moreira PN, Giraldo P, Cozar P, Pozueta J, Jimenez A, Montoliu L, Gutierrez-Adan A (2004) Efficient generation of transgenic mice with intact yeast artificial chromosomes by intracytoplasmic sperm injection. Biol Reprod 71:1943–1947

    Article  PubMed  CAS  Google Scholar 

  • Moreira PN, Pozueta J, Giraldo P, Gutierrez-Adan A, Montoliu L (2006) Generation of yeast artificial chromosome transgenic mice by intracytoplasmic sperm injection. Methods Mol Biol 349:151–161

    PubMed  Google Scholar 

  • Moreira PN, Pozueta J, Perez-Crespo M, Valdivieso F, Gutierrez-Adan A, Montoliu L (2007) Improving the generation of genomic-type transgenic mice by ICSI. Transgenic Res 16:163–168

    Article  PubMed  CAS  Google Scholar 

  • Moscou MJ, Bogdanove AJ (2009) A simple cipher governs DNA recognition by TAL effectors. Science 326:1501

    Article  PubMed  CAS  Google Scholar 

  • Muller B, Grossniklaus U (2010) Model organisms—a historical perspective. J Proteomics 73:2054–2063

    Article  PubMed  CAS  Google Scholar 

  • Muqit MM, Feany MB (2002) Modelling neurodegenerative diseases in Drosophila: a fruitful approach? Nat Rev Neurosci 3:237–243

    Article  PubMed  CAS  Google Scholar 

  • Nagy A (2000) Cre recombinase: the universal reagent for genome tailoring. Genesis 26:99–109

    Article  PubMed  CAS  Google Scholar 

  • Nern A, Pfeiffer BD, Svoboda K, Rubin GM (2011) Multiple new site-specific recombinases for use in manipulating animal genomes. Proc Natl Acad Sci USA 108:14198–14203

    Article  PubMed  CAS  Google Scholar 

  • Newman M, Tucker B, Nornes S, Ward A, Lardelli M (2009) Altering presenilin gene activity in zebrafish embryos causes changes in expression of genes with potential involvement in Alzheimer’s disease pathogenesis. J Alzheimers Dis 16:133–147

    PubMed  CAS  Google Scholar 

  • Niittyla T, Comparot-Moss S, Lue WL, Messerli G, Trevisan M, Seymour MD, Gatehouse JA, Villadsen D, Smith SM, Chen J, Zeeman SC, Smith AM (2006) Similar protein phosphatases control starch metabolism in plants and glycogen metabolism in mammals. J Biol Chem 281:11815–11818

    Article  PubMed  CAS  Google Scholar 

  • Niu Y, Yu Y, Bernat A, Yang S, He X, Guo X, Chen D, Chen Y, Ji S, Si W, Lv Y, Tan T, Wei Q, Wang H, Shi L, Guan J, Zhu X, Afanassieff M, Savatier P, Zhang K, Zhou Q, Ji W (2010) Transgenic rhesus monkeys produced by gene transfer into early-cleavage-stage embryos using a simian immunodeficiency virus-based vector. Proc Natl Acad Sci USA 107:17663–17667

    Article  PubMed  CAS  Google Scholar 

  • Nollen EA, Garcia SM, van Haaften G, Kim S, Chavez A, Morimoto RI, Plasterk RH (2004) Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc Natl Acad Sci USA 101:6403–6408

    Article  PubMed  CAS  Google Scholar 

  • Nornes S, Newman M, Verdile G, Wells S, Stoick-Cooper CL, Tucker B, Frederich-Sleptsova I, Martins R, Lardelli M (2008) Interference with splicing of presenilin transcripts has potent dominant negative effects on presenilin activity. Hum Mol Genet 17:402–412

    Article  PubMed  CAS  Google Scholar 

  • Nornes S, Newman M, Wells S, Verdile G, Martins RN, Lardelli M (2009) Independent and cooperative action of Psen2 with Psen1 in zebrafish embryos. Exp Cell Res 315:2791–2801

    Article  PubMed  CAS  Google Scholar 

  • Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 26:10129–10140

    Article  PubMed  CAS  Google Scholar 

  • Oberstein A, Pare A, Kaplan L, Small S (2005) Site-specific transgenesis by Cre-mediated recombination in Drosophila. Nat Methods 2:583–585

    Article  PubMed  CAS  Google Scholar 

  • Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421

    Article  PubMed  CAS  Google Scholar 

  • Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM (2004) Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43:321–332

    Article  PubMed  CAS  Google Scholar 

  • Ostertag EM, Madison BB, Kano H (2007) Mutagenesis in rodents using the L1 retrotransposon. Genome Biol 8(Suppl 1):S16

    Article  PubMed  Google Scholar 

  • Pallas M, Casadesus G, Smith MA, Coto-Montes A, Pelegri C, Vilaplana J, Camins A (2009) Resveratrol and neurodegenerative diseases: activation of SIRT1 as the potential pathway towards neuroprotection. Curr Neurovasc Res 6:70–81

    Article  PubMed  CAS  Google Scholar 

  • Pan X, Wan H, Chia W, Tong Y, Gong Z (2005) Demonstration of site-directed recombination in transgenic zebrafish using the Cre/loxP system. Transgenic Res 14:217–223

    Article  PubMed  CAS  Google Scholar 

  • Paquet D, Bhat R, Sydow A, Mandelkow EM, Berg S, Hellberg S, Falting J, Distel M, Koster RW, Schmid B, Haass C (2009) A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. J Clin Invest 119:1382–1395

    Article  PubMed  CAS  Google Scholar 

  • Paquet D, Schmid B, Haass C (2010) Transgenic zebrafish as a novel animal model to study tauopathies and other neurodegenerative disorders in vivo. Neurodegener Dis 7:99–102

    Article  PubMed  CAS  Google Scholar 

  • Parkes TL, Elia AJ, Dickinson D, Hilliker AJ, Phillips JP, Boulianne GL (1998) Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat Genet 19:171–174

    Article  PubMed  CAS  Google Scholar 

  • Pesaresi MG, Amori I, Giorgi C, Ferri A, Fiorenzo P, Gabanella F, Salvatore AM, Giorgio M, Pelicci PG, Pinton P, Carri MT, Cozzolino M (2011) Mitochondrial redox signalling by p66Shc mediates ALS-like disease through Rac1 inactivation. Hum Mol Genet 20:4196–4208

    Article  PubMed  CAS  Google Scholar 

  • Piens M, Muller M, Bodson M, Baudouin G, Plumier JC (2010) A short upstream promoter region mediates transcriptional regulation of the mouse doublecortin gene in differentiating neurons. BMC Neurosci 11:64

    Article  PubMed  CAS  Google Scholar 

  • Premsrirut PK, Dow LE, Kim SY, Camiolo M, Malone CD, Miething C, Scuoppo C, Zuber J, Dickins RA, Kogan SC, Shroyer KR, Sordella R, Hannon GJ, Lowe SW (2011) A rapid and scalable system for studying gene function in mice using conditional RNA interference. Cell 145:145–158

    Article  PubMed  CAS  Google Scholar 

  • Rad R, Rad L, Wang W, Cadinanos J, Vassiliou G, Rice S, Campos LS, Yusa K, Banerjee R, Li MA, de la Rosa J, Strong A, Lu D, Ellis P, Conte N, Yang FT, Liu P, Bradley A (2010) PiggyBac transposon mutagenesis: a tool for cancer gene discovery in mice. Science 330:1104–1107

    Article  PubMed  CAS  Google Scholar 

  • Raymond LA, Andre VM, Cepeda C, Gladding CM, Milnerwood AJ, Levine MS (2011) Pathophysiology of Huntington’s disease: time-dependent alterations in synaptic and receptor function. Neuroscience 198:252–273

    Article  PubMed  CAS  Google Scholar 

  • Reaume AG, Howland DS, Trusko SP, Savage MJ, Lang DM, Greenberg BD, Siman R, Scott RW (1996) Enhanced amyloidogenic processing of the beta-amyloid precursor protein in gene-targeted mice bearing the Swedish familial Alzheimer’s disease mutations and a “humanized” Abeta sequence. J Biol Chem 271:23380–23388

    Article  PubMed  CAS  Google Scholar 

  • Remy S, Tesson L, Menoret S, Usal C, Scharenberg AM, Anegon I (2010) Zinc-finger nucleases: a powerful tool for genetic engineering of animals. Transgenic Res 19:363–371

    Article  PubMed  CAS  Google Scholar 

  • Reyon D, Kirkpatrick JR, Sander JD, Zhang F, Voytas DF, Joung JK, Dobbs D, Coffman CR (2011) ZFNGenome: a comprehensive resource for locating zinc finger nuclease target sites in model organisms. BMC Genomics 12:83

    Article  PubMed  CAS  Google Scholar 

  • Ringrose L, Lounnas V, Ehrlich L, Buchholz F, Wade R, Stewart AF (1998) Comparative kinetic analysis of FLP and cre recombinases: mathematical models for DNA binding and recombination. J Mol Biol 284:363–384

    Article  PubMed  CAS  Google Scholar 

  • Robertson HR, Feng G (2011) Annual research review: transgenic mouse models of childhood-onset psychiatric disorders. J Child Psychol Psychiatry 52:442–475

    Article  PubMed  Google Scholar 

  • Roebroek AJ, Gordts PL, Reekmans S (2011) Generation of a series of knock-in alleles using RMCE in ES cells. Methods Mol Biol 693:277–281

    Article  PubMed  CAS  Google Scholar 

  • Roman G (2004) The genetics of Drosophila transgenics. Bioessays 26:1243–1253

    Article  PubMed  CAS  Google Scholar 

  • Romer P, Recht S, Strauss T, Elsaesser J, Schornack S, Boch J, Wang S, Lahaye T (2010) Promoter elements of rice susceptibility genes are bound and activated by specific TAL effectors from the bacterial blight pathogen, Xanthomonas oryzae pv. oryzae. New Phytol 187:1048–1057

    Article  PubMed  CAS  Google Scholar 

  • Ruiz-Opazo N, Kosik KS, Lopez LV, Bagamasbad P, Ponce LR, Herrera VL (2004) Attenuated hippocampus-dependent learning and memory decline in transgenic TgAPPswe Fischer-344 rats. Mol Med 10:36–44

    Article  PubMed  CAS  Google Scholar 

  • Sager JJ, Bai Q, Burton EA (2010) Transgenic zebrafish models of neurodegenerative diseases. Brain Struct Funct 214:285–302

    Article  PubMed  Google Scholar 

  • Sakimura K, Kushiya E, Takahashi Y, Suzuki Y (1987) The structure and expression of neuron-specific enolase gene. Gene 60:103–113

    Article  PubMed  CAS  Google Scholar 

  • Sarov M, Schneider S, Pozniakovski A, Roguev A, Ernst S, Zhang Y, Hyman AA, Stewart AF (2006) A recombineering pipeline for functional genomics applied to Caenorhabditis elegans. Nat Methods 3:839–844

    Article  PubMed  CAS  Google Scholar 

  • Schmitz C, Rutten BP, Pielen A, Schafer S, Wirths O, Tremp G, Czech C, Blanchard V, Multhaup G, Rezaie P, Korr H, Steinbusch HW, Pradier L, Bayer TA (2004) Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer’s disease. Am J Pathol 164:1495–1502

    Article  PubMed  Google Scholar 

  • Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, van Swieten JC (2011) Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J Neurol Neurosurg Psychiatry 82:476–486

    Article  PubMed  Google Scholar 

  • Seibler J, Kleinridders A, Kuter-Luks B, Niehaves S, Bruning JC, Schwenk F (2007) Reversible gene knockdown in mice using a tight, inducible shRNA expression system. Nucleic Acids Res 35:e54

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766

    PubMed  CAS  Google Scholar 

  • Selkoe DJ (2011) Alzheimer’s disease. Cold Spring Harb Perspect Biol 3. doi:10.1101/cshperspect.a004457

  • Semple JI, Garcia-Verdugo R, Lehner B (2010) Rapid selection of transgenic C. elegans using antibiotic resistance. Nat Methods 7:725–727

    Article  PubMed  CAS  Google Scholar 

  • Settivari R, Levora J, Nass R (2009) The divalent metal transporter homologues SMF-1/2 mediate dopamine neuron sensitivity in caenorhabditis elegans models of manganism and parkinson disease. J Biol Chem 284:35758–35768

    Article  PubMed  CAS  Google Scholar 

  • Shan X, Chiang PM, Price DL, Wong PC (2010) Altered distributions of Gemini of coiled bodies and mitochondria in motor neurons of TDP-43 transgenic mice. Proc Natl Acad Sci USA 107:16325–16330

    Article  PubMed  CAS  Google Scholar 

  • Shelbourne PF, Killeen N, Hevner RF, Johnston HM, Tecott L, Lewandoski M, Ennis M, Ramirez L, Li Z, Iannicola C, Littman DR, Myers RM (1999) A Huntington’s disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice. Hum Mol Genet 8:763–774

    Article  PubMed  CAS  Google Scholar 

  • Shulman JM, De Jager PL, Feany MB (2011) Parkinson’s disease: genetics and pathogenesis. Annu Rev Pathol 6:193–222

    Article  PubMed  CAS  Google Scholar 

  • Siegal ML, Hartl DL (2000) Application of Cre/loxP in Drosophila. Site-specific recombination and transgene coplacement. Methods Mol Biol 136:487–495

    PubMed  CAS  Google Scholar 

  • Simard AR, Soulet D, Gowing G, Julien JP, Rivest S (2006) Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49:489–502

    Article  PubMed  CAS  Google Scholar 

  • Skaper SD, Giusti P (2010) Transgenic mouse models of Parkinson’s disease and Huntington’s disease. CNS Neurol Disord Drug Targets 9:455–470

    PubMed  CAS  Google Scholar 

  • Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, Wauters J, Del-Favero J, Cruts M, van Duijn CM, Van Broeckhoven C (2006) APP duplication is sufficient to cause early onset Alzheimer’s dementia with cerebral amyloid angiopathy. Brain 129:2977–2983

    Article  PubMed  Google Scholar 

  • Slow EJ, van Raamsdonk J, Rogers D, Coleman SH, Graham RK, Deng Y, Oh R, Bissada N, Hossain SM, Yang YZ, Li XJ, Simpson EM, Gutekunst CA, Leavitt BR, Hayden MR (2003) Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet 12:1555–1567

    Article  PubMed  CAS  Google Scholar 

  • Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA (2011) Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476:458–461

    Article  PubMed  CAS  Google Scholar 

  • Sora I, Li B, Igari M, Hall FS, Ikeda K (2010) Transgenic mice in the study of drug addiction and the effects of psychostimulant drugs. Ann N Y Acad Sci 1187:218–246

    Article  PubMed  CAS  Google Scholar 

  • Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS One 5:e9979

    Article  PubMed  CAS  Google Scholar 

  • St Johnston D (2002) The art and design of genetic screens: Drosophila melanogaster. Nat Rev Genet 3:176–188

    Article  PubMed  CAS  Google Scholar 

  • Stallings NR, Puttaparthi K, Luther CM, Burns DK, Elliott JL (2010) Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiol Dis 40:404–414

    Article  PubMed  CAS  Google Scholar 

  • Stebbins MJ, Yin JC (2001) Adaptable doxycycline-regulated gene expression systems for Drosophila. Gene 270:103–111

    Article  PubMed  CAS  Google Scholar 

  • Stebbins MJ, Urlinger S, Byrne G, Bello B, Hillen W, Yin JC (2001) Tetracycline-inducible systems for Drosophila. Proc Natl Acad Sci USA 98:10775–10780

    Article  PubMed  CAS  Google Scholar 

  • Sterniczuk R, Antle MC, Laferla FM, Dyck RH (2010) Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: part 2. Behavioral and cognitive changes. Brain Res 1348:149–155

    Article  PubMed  CAS  Google Scholar 

  • Stieger K, Belbellaa B, Le Guiner C, Moullier P, Rolling F (2009) In vivo gene regulation using tetracycline-regulatable systems. Adv Drug Deliv Rev 61:527–541

    Article  PubMed  CAS  Google Scholar 

  • Sureshkumar S, Todesco M, Schneeberger K, Harilal R, Balasubramanian S, Weigel D (2009) A genetic defect caused by a triplet repeat expansion in Arabidopsis thaliana. Science 323:1060–1063

    Article  PubMed  CAS  Google Scholar 

  • Suzuki K, Mansson JE (1998) Animal models of lysosomal disease: an overview. J Inherit Metab Dis 21:540–547

    Article  PubMed  CAS  Google Scholar 

  • Szulc J, Wiznerowicz M, Sauvain MO, Trono D, Aebischer P (2006) A versatile tool for conditional gene expression and knockdown. Nat Methods 3:109–116

    Article  PubMed  CAS  Google Scholar 

  • Takeda J, Izsvak Z, Ivics Z (2008) Insertional mutagenesis of the mouse germline with Sleeping Beauty transposition. Methods Mol Biol 435:109–125

    Article  PubMed  CAS  Google Scholar 

  • Teschendorf D, Link CD (2009) What have worm models told us about the mechanisms of neuronal dysfunction in human neurodegenerative diseases? Mol Neurodegener 4:38

    Article  PubMed  CAS  Google Scholar 

  • Tesson L, Usal C, Menoret S, Leung E, Niles BJ, Remy S, Santiago Y, Vincent AI, Meng X, Zhang L, Gregory PD, Anegon I, Cost GJ (2011) Knockout rats generated by embryo microinjection of TALENs. Nat Biotechnol 29:695–696

    Article  PubMed  CAS  Google Scholar 

  • Thermes V, Grabher C, Ristoratore F, Bourrat F, Choulika A, Wittbrodt J, Joly JS (2002) I-SceI meganuclease mediates highly efficient transgenesis in fish. Mech Dev 118:91–98

    Article  PubMed  CAS  Google Scholar 

  • Thompson LM, Marsh JL (2003) Invertebrate models of neurologic disease: insights into pathogenesis and therapy. Curr Neurol Neurosci Rep 3:442–448

    Article  PubMed  Google Scholar 

  • Thummel R, Burket CT, Brewer JL, Sarras MP Jr, Li L, Perry M, McDermott JP, Sauer B, Hyde DR, Godwin AR (2005) Cre-mediated site-specific recombination in zebrafish embryos. Dev Dyn 233:1366–1377

    Article  PubMed  CAS  Google Scholar 

  • Tong C, Li P, Wu NL, Yan Y, Ying QL (2010) Production of p53 gene knockout rats by homologous recombination in embryonic stem cells. Nature 467:211–213

    Article  PubMed  CAS  Google Scholar 

  • Tong C, Huang G, Ashton C, Li P, Ying QL (2011) Generating gene knockout rats by homologous recombination in embryonic stem cells. Nat Protoc 6:827–844

    Article  PubMed  CAS  Google Scholar 

  • Trancikova A, Ramonet D, Moore DJ (2011) Genetic mouse models of neurodegenerative diseases. Prog Mol Biol Transl Sci 100:419–482

    Article  PubMed  CAS  Google Scholar 

  • Urani A, Gass P (2003) Corticosteroid receptor transgenic mice: models for depression? Ann N Y Acad Sci 1007:379–393

    Article  PubMed  CAS  Google Scholar 

  • Urlinger S, Baron U, Thellmann M, Hasan MT, Bujard H, Hillen W (2000) Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. Proc Natl Acad Sci USA 97:7963–7968

    Article  PubMed  CAS  Google Scholar 

  • van der Putten H, Wiederhold KH, Probst A, Barbieri S, Mistl C, Danner S, Kauffmann S, Hofele K, Spooren WP, Ruegg MA, Lin S, Caroni P, Sommer B, Tolnay M, Bilbe G (2000) Neuropathology in mice expressing human alpha-synuclein. J Neurosci 20:6021–6029

    PubMed  Google Scholar 

  • van Tijn P, Kamphuis W, Marlatt MW, Hol EM, Lucassen PJ (2011) Presenilin mouse and zebrafish models for dementia: focus on neurogenesis. Prog Neurobiol 93:149–164

    Article  PubMed  CAS  Google Scholar 

  • Vander Kooi CW, Taylor AO, Pace RM, Meekins DA, Guo HF, Kim Y, Gentry MS (2010) Structural basis for the glucan phosphatase activity of Starch Excess4. Proc Natl Acad Sci USA 107:15379–15384

    Article  PubMed  CAS  Google Scholar 

  • Venken KJ, He Y, Hoskins RA, Bellen HJ (2006) P[acman]: a BAC transgenic platform for targeted insertion of large DNA fragments in D. melanogaster. Science 314:1747–1751

    Article  PubMed  CAS  Google Scholar 

  • Virata MJ, Zeller RW (2010) Ascidians: an invertebrate chordate model to study Alzheimer’s disease pathogenesis. Dis Model Mech 3:377–385

    Article  PubMed  CAS  Google Scholar 

  • Voytas DF, Joung JK (2009) Plant science. DNA binding made easy. Science 326:1491–1492

    Article  PubMed  CAS  Google Scholar 

  • Walker TL, Yasuda T, Adams DJ, Bartlett PF (2007) The doublecortin-expressing population in the developing and adult brain contains multipotential precursors in addition to neuronal-lineage cells. J Neurosci 27:3734–3742

    Article  PubMed  CAS  Google Scholar 

  • Wang X (2009) Cre transgenic mouse lines. Methods Mol Biol 561:265–273

    Article  PubMed  CAS  Google Scholar 

  • Wang W, Lin C, Lu D, Ning Z, Cox T, Melvin D, Wang X, Bradley A, Liu P (2008) Chromosomal transposition of PiggyBac in mouse embryonic stem cells. Proc Natl Acad Sci USA 105:9290–9295

    Article  PubMed  CAS  Google Scholar 

  • Wang F, Wang X, Yuan CG, Ma J (2010) Generating a prion with bacterially expressed recombinant prion protein. Science 327:1132–1135

    Article  PubMed  CAS  Google Scholar 

  • Watson MR, Lagow RD, Xu K, Zhang B, Bonini NM (2008) A drosophila model for amyotrophic lateral sclerosis reveals motor neuron damage by human SOD1. J Biol Chem 283:24972–24981

    Article  PubMed  CAS  Google Scholar 

  • Wegorzewska I, Baloh RH (2011) TDP-43-based animal models of neurodegeneration: new insights into ALS pathology and pathophysiology. Neurodegener Dis 8:262–274

    Article  PubMed  CAS  Google Scholar 

  • Wegorzewska I, Bell S, Cairns NJ, Miller TM, Baloh RH (2009) TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci USA 106:18809–18814

    Article  PubMed  CAS  Google Scholar 

  • Wen PH, Shao X, Shao Z, Hof PR, Wisniewski T, Kelley K, Friedrich VL Jr, Ho L, Pasinetti GM, Shioi J, Robakis NK, Elder GA (2002) Overexpression of wild type but not an FAD mutant presenilin-1 promotes neurogenesis in the hippocampus of adult mice. Neurobiol Dis 10:8–19

    Article  PubMed  CAS  Google Scholar 

  • Wen PH, Hof PR, Chen X, Gluck K, Austin G, Younkin SG, Younkin LH, DeGasperi R, Gama Sosa MA, Robakis NK, Haroutunian V, Elder GA (2004) The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice. Exp Neurol 188:224–237

    Article  PubMed  CAS  Google Scholar 

  • Wheeler VC, White JK, Gutekunst CA, Vrbanac V, Weaver M, Li XJ, Li SH, Yi H, Vonsattel JP, Gusella JF, Hersch S, Auerbach W, Joyner AL, MacDonald ME (2000) Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice. Hum Mol Genet 9:503–513

    Article  PubMed  CAS  Google Scholar 

  • White JK, Auerbach W, Duyao MP, Vonsattel JP, Gusella JF, Joyner AL, MacDonald ME (1997) Huntingtin is required for neurogenesis and is not impaired by the Huntington’s disease CAG expansion. Nat Genet 17:404–410

    Article  PubMed  CAS  Google Scholar 

  • Wienholds E, van Eeden F, Kosters M, Mudde J, Plasterk RH, Cuppen E (2003) Efficient target-selected mutagenesis in zebrafish. Genome Res 13:2700–2707

    Article  PubMed  CAS  Google Scholar 

  • Williams GC (1957) Pleiotropy, natural-selection, and the evolution of senescence. Evolution 11:398–411

    Article  Google Scholar 

  • Williams A, Sarkar S, Cuddon P, Ttofi EK, Saiki S, Siddiqi FH, Jahreiss L, Fleming A, Pask D, Goldsmith P, O’Kane CJ, Floto RA, Rubinsztein DC (2008) Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway. Nat Chem Biol 4:295–305

    Article  PubMed  CAS  Google Scholar 

  • Wils H, Kleinberger G, Janssens J, Pereson S, Joris G, Cuijt I, Smits V, Ceuterick-de Groote C, Van Broeckhoven C, Kumar-Singh S (2010) TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci USA 107:3858–3863

    Article  PubMed  CAS  Google Scholar 

  • Wirth D, Gama-Norton L, Riemer P, Sandhu U, Schucht R, Hauser H (2007) Road to precision: recombinase-based targeting technologies for genome engineering. Curr Opin Biotechnol 18:411–419

    Article  PubMed  CAS  Google Scholar 

  • Wisniewski T, Boutajangout A (2010) Immunotherapeutic approaches for Alzheimer’s disease in transgenic mouse models. Brain Struct Funct 214:201–218

    Article  PubMed  CAS  Google Scholar 

  • Wisor JP, Edgar DM, Yesavage J, Ryan HS, McCormick CM, Lapustea N, Murphy GM Jr (2005) Sleep and circadian abnormalities in a transgenic mouse model of Alzheimer’s disease: a role for cholinergic transmission. Neuroscience 131:375–385

    Article  PubMed  CAS  Google Scholar 

  • Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J, Hutton M, Feany MB (2001) Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293:711–714

    Article  PubMed  CAS  Google Scholar 

  • Wong AC, Draper BW, Van Eenennaam AL (2011) FLPe functions in zebrafish embryos. Transgenic Res 20:409–415

    Article  PubMed  CAS  Google Scholar 

  • Wood AJ, Lo TW, Zeitler B, Pickle CS, Ralston EJ, Lee AH, Amora R, Miller JC, Leung E, Meng X, Zhang L, Rebar EJ, Gregory PD, Urnov FD, Meyer BJ (2011) Targeted genome editing across species using ZFNs and TALENs. Science 333:307

    Article  PubMed  CAS  Google Scholar 

  • Wu Y, Wu Z, Butko P, Christen Y, Lambert MP, Klein WL, Link CD, Luo Y (2006) Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci 26:13102–13113

    Article  PubMed  CAS  Google Scholar 

  • Xi Y, Noble S, Ekker M (2011) Modeling neurodegeneration in zebrafish. Curr Neurol Neurosci Rep 11:274–282

    Article  PubMed  CAS  Google Scholar 

  • Xu YF, Gendron TF, Zhang YJ, Lin WL, D’Alton S, Sheng H, Casey MC, Tong J, Knight J, Yu X, Rademakers R, Boylan K, Hutton M, McGowan E, Dickson DW, Lewis J, Petrucelli L (2010) Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J Neurosci 30:10851–10859

    Article  PubMed  CAS  Google Scholar 

  • Yae K, Keng VW, Koike M, Yusa K, Kouno M, Uno Y, Kondoh G, Gotow T, Uchiyama Y, Horie K, Takeda J (2006) Sleeping beauty transposon-based phenotypic analysis of mice: lack of Arpc3 results in defective trophoblast outgrowth. Mol Cell Biol 26:6185–6196

    Article  PubMed  CAS  Google Scholar 

  • Yang SH, Cheng PH, Banta H, Piotrowska-Nitsche K, Yang JJ, Cheng EC, Snyder B, Larkin K, Liu J, Orkin J, Fang ZH, Smith Y, Bachevalier J, Zola SM, Li SH, Li XJ, Chan AW (2008) Towards a transgenic model of Huntington’s disease in a non-human primate. Nature 453:921–924

    Article  PubMed  CAS  Google Scholar 

  • Yang D, Wang CE, Zhao B, Li W, Ouyang Z, Liu Z, Yang H, Fan P, O’Neill A, Gu W, Yi H, Li S, Lai L, Li XJ (2010) Expression of Huntington’s disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Hum Mol Genet 19:3983–3994

    Article  PubMed  CAS  Google Scholar 

  • Young JW, Zhou X, Geyer MA (2010) Animal models of schizophrenia. Curr Top Behav Neurosci 4:391–433

    Article  PubMed  Google Scholar 

  • Zan Y, Haag JD, Chen KS, Shepel LA, Wigington D, Wang YR, Hu R, Lopez-Guajardo CC, Brose HL, Porter KI, Leonard RA, Hitt AA, Schommer SL, Elegbede AF, Gould MN (2003) Production of knockout rats using ENU mutagenesis and a yeast-based screening assay. Nat Biotechnol 21:645–651

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Nash L, Fisher AL (2008) A simplified, robust, and streamlined procedure for the production of C. elegans transgenes via recombineering. BMC Dev Biol 8:119

    Article  PubMed  CAS  Google Scholar 

  • Zhang S, Feany MB, Saraswati S, Littleton JT, Perrimon N (2009) Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntington’s disease model. Dis Model Mech 2:247–266

    Article  PubMed  CAS  Google Scholar 

  • Zhang F, Cong L, Lodato S, Kosuri S, Church GM, Arlotta P (2011a) Efficient construction of sequence-specific TAL effectors for modulating mammalian transcription. Nat Biotechnol 29:149–153

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Kashyap L, Ferguson AA, Fisher AL (2011b) The production of C. elegans transgenes via recombineering with the galK selectable marker. J Vis Exp. doi:10.3791/2331

  • Zhou H, Huang C, Yang M, Landel CP, Xia PY, Liu YJ, Xia XG (2009) Developing tTA transgenic rats for inducible and reversible gene expression. Int J Biol Sci 5:171–181

    Article  PubMed  CAS  Google Scholar 

  • Zhou H, Huang C, Chen H, Wang D, Landel CP, Xia PY, Bowser R, Liu YJ, Xia XG (2010) Transgenic rat model of neurodegeneration caused by mutation in the TDP gene. PLoS Genet 6:e1000887

    Article  PubMed  CAS  Google Scholar 

  • Zhuo L, Sun B, Zhang CL, Fine A, Chiu SY, Messing A (1997) Live astrocytes visualized by green fluorescent protein in transgenic mice. Dev Biol 187:36–42

    Article  PubMed  CAS  Google Scholar 

  • Ziemienowicz A (2010) Plant transgenesis. Methods Mol Biol 631:253–268

    Article  PubMed  CAS  Google Scholar 

  • Zigman WB, Schupf N, Sersen E, Silverman W (1996) Prevalence of dementia in adults with and without Down syndrome. Am J Ment Retard 100:403–412

    PubMed  CAS  Google Scholar 

  • Zimmerman L, Parr B, Lendahl U, Cunningham M, McKay R, Gavin B, Mann J, Vassileva G, McMahon A (1994) Independent regulatory elements in the nestin gene direct transgene expression to neural stem cells or muscle precursors. Neuron 12:11–24

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Supported by the Alzheimer’s Association (IIRG-07-57318), Department of Veterans Affairs (1 I01 BX000342-01) and the National Institute on Aging (P50 AG005138).

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Authors and Affiliations

  1. Research and Development Service, 3F-20, James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA

    Miguel A. Gama Sosa & Rita De Gasperi

  2. Neurology Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY, USA

    Gregory A. Elder

  3. Department of Psychiatry, Mount Sinai School of Medicine of New York University, New York, NY, USA

    Miguel A. Gama Sosa, Rita De Gasperi & Gregory A. Elder

  4. Department of Neurology, Mount Sinai School of Medicine of New York University, New York, NY, USA

    Gregory A. Elder

  5. The Friedman Brain Institute, Mount Sinai School of Medicine of New York University, New York, NY, USA

    Miguel A. Gama Sosa, Rita De Gasperi & Gregory A. Elder

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  1. Miguel A. Gama Sosa
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Gama Sosa, M.A., De Gasperi, R. & Elder, G.A. Modeling human neurodegenerative diseases in transgenic systems. Hum Genet 131, 535–563 (2012). https://doi.org/10.1007/s00439-011-1119-1

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