An Essential Role for DYF-11MIP-T3 in Assembling Functional Intraflagellar Transport Complexes 英文参考文献.docVIP

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An Essential Role for DYF-11MIP-T3 in Assembling Functional Intraflagellar Transport Complexes 英文参考文献.doc

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An Essential Role for DYF-11MIP-T3 in Assembling Functional Intraflagellar Transport Complexes 英文参考文献

AnEssentialRoleforDYF-11/MIP-T3inAssembling FunctionalIntraflagellarTransportComplexes ChunmeiLi1.,PeterN.Inglis1.,CarmenC.Leitch2,EvgeniEfimenko3,NorannA.Zaghloul2,CalvinA. Mok4,5,EricaE.Davis2,NathanJ.Bialas1,MichaelP.Healey1,EliseHe′on5,MeiZhen4,PeterSwoboda3, NicholasKatsanis2,MichelR.Leroux1* 1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada, 2McKusick-Nathans Institute of Genetic Medicine, JohnsHopkinsUniversitySchoolofMedicine,Baltimore,Maryland,UnitedStatesofAmerica,3KarolinskaInstitute,DepartmentofBiosciencesandNutrition,So¨derto¨rn UniversityCollege,SchoolofLifeSciences,Huddinge,Sweden,4SamuelLunenfeldResearchInstitute,MountSinaiHospitalandDepartmentofMicrobiologyandMedical Genetics,UniversityofToronto,Ontario,Canada,5DepartmentofOphthalmologyandVisionSciences,TheHospitalforSickChildrenandUniversityofToronto,Toronto, Ontario,Canada Abstract MIP-T3isahumanproteinfoundpreviouslytoassociatewithmicrotubules andthekinesin-interacting neuronalprotein DISC1 (Disrupted-in-Schizophrenia 1), butwhose cellular function(s)remains unknown. Herewedemonstrate that the C. elegansMIP-T3orthologDYF-11isanintraflagellartransport(IFT)proteinthatplaysacriticalroleinassemblingfunctional kinesinmotor-IFTparticlecomplexes.Wehaveclonedalossoffunctiondyf-11mutantinwhichseveralkeycomponentsof theIFTmachinery,includingKinesin-II,aswellasIFTsubcomplexAandBproteins,failtoenterciliaryaxonemesand/or mislocalize,resultingincompromisedciliarystructuresandsensoryfunctions,andabnormallipidaccumulation.Analysesin differentmutantbackgroundsfurthersuggestthatDYF-11functionsasanovelcomponentofIFTsubcomplexB.Consistent withanevolutionarilyconservedcilia-associatedrole,mammalianMIP-T3localizestobasalbodiesandcilia,andzebrafish mipt3functionssynergisticallywiththeBardet-BiedlsyndromeproteinBbs4toensurepropergastrulation,akeycilium-and basalbody-dependentdevelopmentalprocess.OurfindingsthereforeimplicateMIP-T3inapreviouslyunknownbu