An ENU-Induced Mutation of Nrg1 Causes Dilated Pupils and a Reduction in Muscarinic Receptors in the Sphincter Pupillae 英文参考文献.docVIP

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An ENU-Induced Mutation of Nrg1 Causes Dilated Pupils and a Reduction in Muscarinic Receptors in the Sphincter Pupillae 英文参考文献.doc

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An ENU-Induced Mutation of Nrg1 Causes Dilated Pupils and a Reduction in Muscarinic Receptors in the Sphincter Pupillae 英文参考文献

AnENU-InducedMutationofNrg1CausesDilatedPupils andaReductioninMuscarinicReceptorsintheSphincter Pupillae BingChen1,2,KeLi2,FenliZhang2,GuoqinZhai2,WenGong2,SujingQiang2,ZhengfengXue1,2* 1ComparativeMedicineCenter,YangzhouUniversity,Jiangsu,Yangzhou,China,2CollegeofVeterinaryMedicine,YangzhouUniversity,Jiangsu,Yangzhou,China Abstract Background:N-ethyl-N-nitrosourea(ENU)-inducedmutagenesisisapowerfultoolforthestudyofgenefunctionandthe generation of human disease models. A large number of mouse mutants obtained by ENU-induced mutagenesis with a varietyofphenotypeshavebeenrecovered.However,aftergeneticconfirmationtesting,onlyapproximately50%ofthe abnormalphenotypeswerefoundtobeheritable. Methodology/PrincipalFindings:Amousemutant,Dp1,withadilatedpupilphenotypewasinducedwithanN-ethyl-N- nitrosourea(ENU)mutagenesisstrategy.SequenceanalysisforNrg1revealsaG.AbasesubstitutionthatflanksexonE59, encodingforanEGFbdomain,inthe59splicedonorsite.ThemutationaffectsbutdoesnotabolishthesplicingofEGFb- typeNrg1mRNAinDp1miceandproducesseveraldifferenttranscriptsbyactivatingother,crypticsplicesites.Thesetypes ofproteinisoformsareexpected,andtheresultshowsthat,inthemutant,theeffectisadecreaseinbutnotanelimination ofthehighaffinityEGFb-typeNrg1isoforms.Thisispartiallycompensatedforbyanincreaseinexpressionofthelowaffinity alphaformsorinactiveproteins,suggestingthatthemutationresultsinahypomorphicallele.Interestingly,geneticmodel testingshowsthatDp1isamutationthatresultsinadilatedpupilphenotypethatisinheritedwithverylowpenetrance whenheterozygousandwithcompletepenetrancewhenhomozygous.Pharmacologicalandimmunohistochemicaltests showareductionofmuscarinic(M)receptorsinthesphincterpupillaeofDp1mice,whichisamajorcauseofdilatedpupils. Conclusions/Significance:ThisstudyisthefirstreportofanNrg1mutationbeingassociatedwithadilatedpupilphenotype andthereductionofMreceptors. Thisreportmayhelpinestablishingmoremutantmouselinesandmodelsofhuman geneticdiseaseandcanbeappliedtootherorganisms.Dp1micear