Genetically modified mouse - Wikipedia

A genetically modified mouse or genetically engineered mouse model (GEMM) is a mouse (Mus musculus) that has had its genome altered through the use of ... Geneticallymodifiedmouse FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch Thegeneticallymodifiedmouseinwhichageneaffectinghairgrowthhasbeenknockedout(left),shownnexttoanormallabmouse. Ageneticallymodifiedmouseorgeneticallyengineeredmousemodel(GEMM)[1]isamouse(Musmusculus)thathashaditsgenomealteredthroughtheuseofgeneticengineeringtechniques.Geneticallymodifiedmicearecommonlyusedforresearchorasanimalmodelsofhumandiseases,andarealsousedforresearchongenes.Togetherwithpatient-derivedxenografts(PDXs),GEMMsarethemostcommoninvivomodelsincancerresearch.Bothapproachesareconsideredcomplementaryandmaybeusedtorecapitulatedifferentaspectsofdisease.[2]GEMMsarealsoofgreatinterestfordrugdevelopment,astheyfacilitatetargetvalidationandthestudyofresponse,resistance,toxicityandpharmacodynamics.[3] Contents 1History 2Methods 3Uses 4References 5Externallinks History[edit] In1974BeatriceMintzandRudolfJaenischcreatedthefirstgeneticallymodifiedanimalbyinsertingaDNAvirusintoanearly-stagemouseembryoandshowingthattheinsertedgeneswerepresentineverycell.[4]However,themicedidnotpassthetransgenetotheiroffspring,andtheimpactandapplicabilityofthisexperimentwere,therefore,limited.In1981thelaboratoriesofFrankRuddle[5]fromYaleUniversity,FrankCostantiniandElizabethLacyfromOxford,andRalphL.BrinsterandRichardPalmiterincollaborationfromtheUniversityofPennsylvaniaandtheUniversityofWashingtoninjectedpurifiedDNAintoasingle-cellmouseembryoutilizingtechniquesdevelopedbyBrinsterinthe1960sand1970s,showingtransmissionofthegeneticmaterialtosubsequentgenerationsforthefirsttime.[6][7][8]Duringthe1980s,PalmiterandBrinsterdevelopedandledthefieldoftransgenesis,refiningmethodsofgermlinemodificationandusingthesetechniquestoelucidatetheactivityandfunctionofgenesinawaynotpossiblebeforetheiruniqueapproach.[9] Methods[edit] Therearetwobasictechnicalapproachestoproducegeneticallymodifiedmice.Thefirstinvolvespronuclearinjection,atechniquedevelopedandrefinedbyRalphL.Brinsterinthe1960sand1970s,intoasinglecellofthemouseembryo,whereitwillrandomlyintegrateintothemousegenome.[10]Thismethodcreatesatransgenicmouseandisusedtoinsertnewgeneticinformationintothemousegenomeortoover-expressendogenousgenes.Thesecondapproach,pioneeredbyOliverSmithiesandMarioCapecchi,involvesmodifyingembryonicstemcellswithaDNAconstructcontainingDNAsequenceshomologoustothetargetgene.EmbryonicstemcellsthatrecombinewiththegenomicDNAareselectedforandtheyaretheninjectedintothemiceblastocysts.[11]Thismethodisusedtomanipulateasinglegene,inmostcases"knockingout"thetargetgene,althoughincreasinglymoresubtleandcomplexgeneticmanipulationcanoccur(e.g.humanisationofaspecificprotein,oronlychangingsinglenucleotides). Uses[edit] Transgenicmiceexpressinggreenfluorescentprotein,whichglowsgreenunderbluelight.Thecentralmouseiswild-type. Geneticallymodifiedmiceareusedextensivelyinresearchasmodelsofhumandisease.[12]Miceareausefulmodelforgeneticmanipulationandresearch,astheirtissuesandorgansaresimilartothatofahumanandtheycarryvirtuallyallthesamegenesthatoperateinhumans.[13]Theyalsohaveadvantagesoverothermammals,inregardstoresearch,inthattheyareavailableinhundredsofgeneticallyhomogeneousstrains.[13]Also,duetotheirsize,theycanbekeptandhousedinlargenumbers,reducingthecostofresearchandexperiments.[13]Themostcommontypeistheknockoutmouse,wheretheactivityofasingle(orinsomecasesmultiple)genesareremoved.Theyhavebeenusedtostudyandmodelobesity,heartdisease,diabetes,arthritis,substanceabuse,anxiety,aging,temperatureandpainreception,andParkinsondisease.[14][15]Transgenicmicegeneratedtocarryclonedoncogenesandknockoutmicelackingtumorsuppressinggeneshaveprovidedgoodmodelsforhumancancer.Hundredsoftheseoncomicehavebeendevelopedcoveringawiderangeofcancersaffectingmostorgansofthebodyandtheyarebeingrefinedtobecomemorerepresentativeofhumancancer.[9]Thediseasesymptomsandpotentialdrugsortreatmentscanbetestedagainstthesemousemodels. Amousehasbeengeneticallyengineeredtohaveincreasedmusclegrowthandstrengthbyoverexpressingtheinsulin-likegrowthfactorI(IGF-I)indifferentiatedmusclefibers.[16][17]Anothermousehashadagenealteredthatisinvolvedinglucosemetabolismandrunsfaster,liveslonger,ismoresexuallyactiveandeatsmorewithoutgettingfatterthantheaveragemouse(seeMetabolicsupermice).[18][19]AnothermousehadtheTRPM8receptorblockedorremovedinastudyinvolvingcapsaicinandmenthol.[15]WiththeTRPM8receptorremoved,themousewasunabletodetectsmallchangesintemperatureandthepainassociatedwithit.[15] Greatcareshouldbetakenwhendecidinghowtousegeneticallymodifiedmiceinresearch.[20]Evenbasicissueslikechoosingthecorrect"wild-type"controlmousetouseforcomparisonaresometimesoverlooked.[21] References[edit] ^Singh,M.;Murriel,C.L.;Johnson,L.(16May2012)."GeneticallyEngineeredMouseModels:ClosingtheGapbetweenPreclinicalDataandTrialOutcomes".CancerResearch.72(11):2695–2700.doi:10.1158/0008-5472.CAN-11-2786.PMID 22593194. ^Abate-Shen,C.;Pandolfi,P.P.(30September2013)."EffectiveUtilizationandAppropriateSelectionofGeneticallyEngineeredMouseModelsforTranslationalIntegrationofMouseandHumanTrials".ColdSpringHarborProtocols.2013(11):1006–1011.doi:10.1101/pdb.top078774.PMC 4382078.PMID 24173311. ^Sharpless,NormanE.;DePinho,RonaldA.(September2006)."Themightymouse:geneticallyengineeredmousemodelsincancerdrugdevelopment".NatureReviewsDrugDiscovery.5(9):741–754.doi:10.1038/nrd2110.ISSN 1474-1784.PMID 16915232.S2CID 7254415. ^Jaenisch,R.;Mintz,B.(1974)."Simianvirus40DNAsequencesinDNAofhealthyadultmicederivedfrompreimplantationblastocystsinjectedwithviralDNA".Proc.Natl.Acad.Sci.71(4):1250–1254.Bibcode:1974PNAS...71.1250J.doi:10.1073/pnas.71.4.1250.PMC 388203.PMID 4364530. ^Kucherlapati,Raju;Leinwand,LeslieA.(2013)."FrankRuddle(1929–2013".AmericanJournalofHumanGenetics.92(6):839–840.doi:10.1016/j.ajhg.2013.05.012.PMC 3675234.PMID 24242788. ^Gordon,J.;Ruddle,F.(1981)."Integrationandstablegermlinetransmissionofgenesinjectedintomousepronuclei".Science.214(4526):1244–6.Bibcode:1981Sci...214.1244G.doi:10.1126/science.6272397.PMID 6272397. ^Costantini,F.;Lacy,E.(1981)."Introductionofarabbitβ-globingeneintothemousegermline".Nature.294(5836):92–4.Bibcode:1981Natur.294...92C.doi:10.1038/294092a0.PMID 6945481.S2CID 4371351. ^BrinsterR,ChenHY,TrumbauerM,SenearAW,WarrenR,PalmiterRD(1981)."Somaticexpressionofherpesthymidinekinaseinmicefollowinginjectionofafusiongeneintoeggs".Cell.27(1Pt2):223–231.doi:10.1016/0092-8674(81)90376-7.PMC 4883678.PMID 6276022. ^abDouglasHanahan;ErwinF.Wagner;RichardD.Palmiter(2007)."Theoriginsofoncomice:ahistoryofthefirsttransgenicmicegeneticallyengineeredtodevelopcancer".GenesDev.21(18):2258–2270.doi:10.1101/gad.1583307.PMID 17875663. ^Gordon,J.W.,Scangos,G.A,Plotkin,D.J.,Barbosa,J.A.andRuddleF.H.(1980)."GenetictransformationofmouseembryosbymicroinjectionofpurifiedDNA".Proc.Natl.Acad.Sci.USA.77(12):7380–7384.Bibcode:1980PNAS...77.7380G.doi:10.1073/pnas.77.12.7380.PMC 350507.PMID 6261253.{{citejournal}}:CS1maint:multiplenames:authorslist(link) ^ThomasKR,CapecchiMR(1987)."Site-directedmutagenesisbygenetargetinginmouseembryo-derivedstemcells".Cell.51(3):503–12.doi:10.1016/0092-8674(87)90646-5.PMID 2822260.S2CID 31961262. ^"Background:ClonedandGeneticallyModifiedAnimals".CenterforGeneticsandSociety.April14,2005.ArchivedfromtheoriginalonNovember23,2016.RetrievedJuly11,2010. ^abcHofker,MartenH.;Deursen,Janvan(2002).TransgenicMouse.Totowa,NewJersey:HumanaPress.pp. 1.ISBN 0-89603-915-3. ^"KnockoutMice".NationHumanGenomeResearchInstitute.2009. ^abcJulius,David."Howpeppersandpeppermintidentifiedsensoryreceptorsfortemperatureandpain".iBiology.Retrieved2020-05-14. ^McPherron,A.;Lawler,A.;Lee,S.(1997)."RegulationofskeletalmusclemassinmicebyanewTGF-betasuperfamilymember".Nature.387(6628):83–90.Bibcode:1997Natur.387...83M.doi:10.1038/387083a0.PMID 9139826.S2CID 4271945. ^ElisabethR.Barton-Davis;DariaI.Shoturma;AntonioMusaro;NadiaRosenthal;H.LeeSweeney(1998)."Viralmediatedexpressionofinsulin-likegrowthfactorIblockstheaging-relatedlossofskeletalmusclefunction".PNAS.95(26):15603–15607.Bibcode:1998PNAS...9515603B.doi:10.1073/pnas.95.26.15603.PMC 28090.PMID 9861016. ^"Geneticallyengineeredsupermousestunsscientists".AAP.November3,2007. ^HakimiP,YangJ,CasadesusG,MassillonD,Tolentino-SilvaF,NyeC,CabreraM,HagenD,UtterC,BaghdyY,JohnsonDH,WilsonDL,KirwanJP,KalhanSC,HansonRW(2007)."Overexpressionofthecytosolicformofphosphoenolpyruvatecarboxykinase(GTP)inskeletalmusclerepatternsenergymetabolisminthemouse".JournalofBiologicalChemistry.282(45):32844–32855.doi:10.1074/jbc.M706127200.PMC 4484620.PMID 17716967. ^Crusio,W.E.;Goldowitz,D.;Holmes,A.;Wolfer,D.(2009)."Standardsforthepublicationofmousemutantstudies".Genes,BrainandBehavior.8(1):1–4.doi:10.1111/j.1601-183X.2008.00438.x.PMID 18778401.S2CID 205853147. ^MohammedBourdi;JohnS.Davies;LanceR.Pohl(2011)."MispairingC57BL/6SubstrainsofGeneticallyEngineeredMiceandWild-TypeControlsCanLeadtoConfoundingResultsasItDidinStudiesofJNK2inAcetaminophenandConcanavalinALiverInjury".ChemicalResearchinToxicology.24(6):794–796.doi:10.1021/tx200143x.PMC 3157912.PMID 21557537. 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