哺乳动物精子干细胞相关基因

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日期: 2004-05-25 今日/总浏览: 1/414: j9 n! S! x9 C' u3 c3 a

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Researchershaveidentifiedthefirstgenelinkedtotheproductivityofthestemcellsthatproducesperminmammals.Thediscoverywasmadebyapplyingthelatestlaboratorymethodstoastrainofmicerestoredfromembryosfrozensincetheearly70s.Thefindings,whichcouldsomedayhaveimplicationsforinfertility,contraception,andstemcelltransplantationtherapy,willbepublishedintheJuneissueofNatureGenetics.: q% x* }" u. Z6 g- C: W
Whatresearchersaretryingtodoisunravelthemysteryoftheadultgermstemcellsinmaletesticles,whicharecapableofproducinganaverageof1,500spermduringeveryhumanheartbeat?oranaverageof130millionspermaday.% O7 Q) v- V9 P) D1 a& m4 T& Z
Theaveragemanwillmaintainahighlevelofspermproductionfrompubertyonward,fordecadeafterdecade.Tomaintainthathighaspermoutput,youneedmanyfunctioningstemcells.Butthestemcellshavetowalkatightropeandcarefullybalancethedecisiontobecomeaspermwiththedecisiontostayastemcell,sothatthespermoutputismaintainedforalloftheseyears,saidDr.RobertBraun,associateprofessorofgenomesciencesintheUniversityofWashingtonSchoolofMedicine.
6 v- K0 z7 ]8 O7 W0 Z2 g: CTheresearchwasfundedinpartbytheNationalInstituteofChildHealthandHumanDevelopment'sContraceptiveDevelopmentResearchCentersProgram.* s7 `0 h* V' ~' W2 D
Stemcellsarecellsthatarenotdifferentiated?thatis,theyhavenotacquiredaparticulartype(suchaslungcells,orbloodcells).Researcherscallstemcells'pluripotent'cells,meaningthatanygivenstemcellcanbecomeanyofseveraltypes.Intheearlyembryo,embryonicstemcellsgiverisetoallofthecelltypesintheorganism,includingadultstemcells,whichcontinuallyreplacecellsintheadulttissuesthatdieordifferentiateintomorematurecellslikeredbloodcells.Intheadulttesticles,thegermstemcellscanproducemoregermstemcells,butcanalsoproducedaughtercellsthatgoontobecomesperm.Butresearchersdonotknowhowthegermstemcellsdecidewhethertocreateothergermstemcellsorcommittobecomingsperm.Theworkingsofstemcellswithinthetesticlesarenotwellunderstoodinmammals,thoughafewgeneshavebeenlinkedtostemcellself-renewalinthefruitfly,whichhasasimpleranatomicalstructure.
% j0 w/ a. T8 e4 SBraun'slaboratorystudiesmammals.Oneofhispredoctoralstudents,BillBuaas,wasreadingjournalarticlesfromdecadesagowhenhecameacrossadescriptionofamutantlineofmicethatoriginatedinthe1950s.Thesemicewerestudiedatthetimefortheirlimbdeformities,buttherewasapassingreferenceintheliteraturetohowthemicewerefertileforalittlewhile,butthenbecameinfertile.BuaasandBraunagreedthatitsoundedasifthemicewerebornwithgermstemcells,thecellsthatproducesperm,butthenlosttheirgermlineearlyinpuberty.Afteraseriesoftests,theresearchersconcludedthatbecauseofthemutation,thecellsweremorelikelytoconvertfromgermstemcellsintosperm,thantoproducemoregermstemcellstokeeptheprocessgoing.
) i9 p+ Q% ^' o2 q+ U  r) [( |ThisluxoidstrainofmicewasfirstidentifiedbyMargaretC.GreenoftheUniversityofOhio.Green,awell-knownmousegeneticistwhodiedseveralyearsago,hadseveralembryosfromthe35thgenerationofthemicefrozenattheJacksonLaboratoryinMaine,theworld'slargestmutantmouseresourcecenter.TheUWresearcherscontactedTheJacksonLaboratoryfortheembryos,andstafftherebroughtthestrainbacktolifeafterthe30-yearfreeze.
9 d' k5 @! L1 J/ \& rBackinthe70s,researcherswereabletopositiontheluxoidmutationonmousechromosome9.Usingmodernmethodsandthepublishedmousegenomesequence,UWresearcherswereabletoidentifythemutationatagenecalledZFP145,whichproducestheproteinPLZF.UsingafluorescentantibodyagainstthePLZFprotein,theresearcherswereabletoshowdirectlythatPLZFisexpressedintheadultgermstemcells.Theresearcherswentontoshowthatanotherprotein,OCT4,whichfunctionstomaintainthestemcellsintheearlyembryoandinculturedembryonicstemcells,isalsopresentintheadultgermstemcell.Thisimportantfindingconfirmsearlierpublishedstudiessuggestingthattheadultgermstemcellsarenotfarremovedfromembryonicstemcells.
& e/ M3 X3 S3 f. r1 w; OIdentificationofthemutationmayhavesignificanteffectsforbothinfertilityandcontraceptionresearch.Intermsofinfertility,researchersmaysomedayfindalinkbetweenthegeneandagraduallossofgermcellswithinthehumantestes,Braunsaid.It'spossiblethatthemutationmaytiptheinfertileman'sstemcellstowarddifferentiation:theirstemcellsproducespermforawhile,andthenaredepletedandbecomeinfertile?ashappensintheluxoidmice.Intheory,thatandotherdiscoveriesmightbeusedtofashionatherapytorescuehumangermcellsandmaintainspermproduction.0 N3 V; C. p+ x7 U) O
Inthesameway,anypracticalimplicationsforcontraceptiveresearcharemanyyearsaway,Braunsaiduxoidappearstobeimportantinthecells'decisionwhethertoremainastemcell,ordifferentiate.Ifwecanunderstandalltheplayersthenmaybewecoulddevelopadrugthatcouldblockthedecisiontobecomesperm?acontraceptivethatwouldbereversible.However,Braunstressedthatsuchproductsaremany,manyyearsawayandwillrequireconsiderableresearch.4 a- g& P& C$ c' y; y9 b0 e
Researchersalsohopetosomedaybeabletoreversethedevelopmentalprocessandcreateembryonicstemcellsfromadultgermstemcells.Embryonicstemcellsaremorepluripotentthanadultstemcells.Theembryonicstemcellscouldthenbeusedintransplantationtherapyinpatientswithdegenerativediseasesofothertissues.
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作者: ( D7 E/ }4 f. s/ O
来源: University of Washington
( M" P3 H+ M" ^" t6 N7 f+ Y发布者: 刘斌