Deletion of MgcRacGAP in the male germ cells impairs spermatogenesis and causes male sterility in the mouse

摘要

MgcRacGAP(RACGAP1)isaGTPaseActivatingProtein(GAP),highlyproducedinthemouseembryonicbrainandinthehumanandmousepost-nataltestis.MgcRacGAPnegativelycontrolstheactivityofRacandCdc42,whicharekeymolecularswitchesactingonthemicrotubuleandactincytoskeletonandcontrollingvariouscellprocessessuchasproliferation,adhesionandmotility.PreviousstudiesdemonstratedthatMgcRacGAPplaysacriticalroleinthecytokinesisofsomaticcells;hencehomozygousinactivationofthegeneinthemouseandmutationinemCaenorhabditiselegans/emledtoembryoniclethalityduetotheinabilityofMgcRacGAP-nullembryostoassemblethecentralspindleandtocompletecytokinesis./ppid="sp0060"Inthetestis,thegermcellsdonotcompletecytokinesisandremainconnectedasasyncytiumthroughouttheentireprocessofspermatogenesis.Interestingly,MgcRacGAPwasshowntolocatetotheintercellularbridges,connectingthesegermcells.Inordertodeterminethefunction(s)ofMgcRacGAPinthemalegermline,wegeneratedaconditionalknock-outmouseusingStra8promoterdrivenCrerecombinasetoinducethespecificdeletionofemMgcRacGAP/eminthepre-meioticgermcells.WefoundthattheabsenceofMgcRacGAPinducedagermlinedepletionandmalesterility.ConsistentwiththeroleofMgcRacGAPintheestablishmentofthecytoplasmconstrictionduringcytokinesisofthesomaticcells,weobservedthatemMgcRacGAP/emdeletioninthegermcellspreventedtheformationoftheintercellularbridgesandinducedaproliferationarrest.WhileweassumethatinheritedhomozygouslossoffunctionmutationsinemMgcRacGAP/emwouldbelethalinhuman,emdenovo/emmutationsinthetestismightaccountforsomecasesofnon-obstructiveoligo-and/orazoo-spermiasyndromes,whosegeneticcausesarealtogetherstillpoorlydefined./p/div