RAB-Like 2 Has an Essential Role in Male Fertility, Sperm Intra-Flagellar Transport, and Tail Assembly 英文参考文献.docVIP

RAB-Like2HasanEssentialRoleinMaleFertility,Sperm Intra-FlagellarTransport,andTailAssembly JenniferC.Y.Lo1,DuangpornJamsai1,AnneE.O’Connor1,ClaireBorg1,BrettJ.Clark1, JamesC.Whisstock2,MarkC.Field3,VickiAdams4,TomomotoIshikawa1,R.JohnAitken5, BelindaWhittle4,ChristopherC.Goodnow4,ChristopherJ.Ormandy6,MoiraK.O’Bryan1* 1DepartmentofAnatomyandDevelopmentalBiology,MonashUniversity,Melbourne,Victoria,Australia,2DepartmentofBiochemistryandMolecularBiology,Monash University,Melbourne,Victoria,Australia,3TheDepartmentofPathology,UniversityofCambridge,Cambridge,UnitedKingdom,4AustralianPhenomicsFacility,John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia, 5School of Environmental and Life Sciences, University of Newcastle, Callaghan,NewSouthWales,Australia,6TheGarvanInstituteofMedicalResearch,Darlinghurst,NewSouthWales,Australia Abstract A significant percentage of young men are infertile and, for the majority, the underlying cause remains unknown. Male infertilityis,however,frequentlyassociatedwithdefectivespermmotility,whereinthespermtailisamodifiedflagella/cilia. Conversely, a greater understanding of essential mechanisms involved in tail formation may offer contraceptive opportunities,ormorebroadly,therapeuticstrategiesforglobalciliadefects.HerewehaveidentifiedRab-like2(RABL2)as anessentialrequirementforspermtailassemblyandfunction.RABL2isamemberofapoorlycharacterizedcladeofthe RASGTPasesuperfamily.RABL2ishighlyenrichedwithindevelopingmalegermcells,whereitlocalizestothemid-pieceof the sperm tail. Lesser amounts of Rabl2 mRNA were observed in other tissues containing motile cilia. Using a co- immunoprecipitationapproachandRABL2affinitycolumnsfollowedbyimmunochemistry,wedemonstratedthatwithin developing haploid germ cells RABL2 interacts with intra-flagella transport (IFT) proteins and delivers a specific set of effector (cargo) proteins, including key members of the glycolytic pathway, to the sperm tail.RABL2 binding to effe