VI胚層發(fā)育與器官系統(tǒng)發(fā)生

VI胚層發(fā)育與器官系統(tǒng)發(fā)生第1頁(yè)/共43頁(yè)Thevertebratelimbdevelopmentisaparticularlygoodsysteminwhichtostudypatternformationduringorganogenesis(I)

Thevertebratelimbisacomplexorganwiththreedevelopmentalaxes:theproximo-distalaxisrunningfromthebaseofthelimbtothetip,theantero-posterioraxisrunningparallelwiththebodyAPaxis,andthedorso-ventralaxisrunningfromthebackofthehandtothepalm.

Thus,thelimbdevelopmentisaparticularlygoodsysteminwhichtostudypatternformation

Sincethelimbs,unlikeheartorbrain,arenotessentialforembryoniclife,onecanexperimentallyremoveortransplantpartsofthedevelopinglimb,orcreatelimb-specificmutantswithoutinterferingwiththevitalprocessesoftheorganism.Thisisgoodadvantageofstudyingpatternformationinorganogenesis

第2頁(yè)/共43頁(yè)Thevertebratelimbdevelopmentisaparticularlygoodsysteminwhichtostudypatternformationduringorganogenesis(II)

Thelimbisagoodmodelforstudyingcellularinteractionswithinastructurecontainingalargenumberofcells,andforelucidatingtheroleofintercellularsignalingindevelopment.Recently,particularsignalproteinshavebeenidentifiedtofunctioninpatterningalongeachofthreelimbaxes:

FGFfamilyinPr-Daxialpatterning

Sonichedgehog(Shh)proteininA-Paxialpatterning

Wnt7ainD-Vaxialpatterning

第3頁(yè)/共43頁(yè)Thevertebratelimbdevelopsfromalimbbud第4頁(yè)/共43頁(yè)3Thelimbdevelopment3.1Specificationandformationofthelimbbud3.2Thelimboutgrowthandgenerationoftheproximal-distalaxis3.3Theanterior-posterioraxialpatterning3.4Patterningthedorsal-ventralaxis3.5Coordinatingthethreeaxes3.6DevelopmentofthedigitsDevelopmentofthevertebratelimb第5頁(yè)/共43頁(yè)3Thelimbdevelopment3.1Specificationandformationofthelimbbud3.2Thelimboutgrowthandgenerationoftheproximal-distalaxis3.3Theanterior-posterioraxialpatterning3.4Patterningthedorsal-ventralaxis3.5Coordinatingthethreeaxes3.6DevelopmentofthedigitsDevelopmentofthevertebratelimb第6頁(yè)/共43頁(yè)Thevertebratelimbdevelopsfromalimbbud第7頁(yè)/共43頁(yè)P(yáng)roliferationofmesodermalcellsfromthelateralplatemesodermcausesthelimbbudtobulgeoutwardWhilethelateralplatemesodermalcellsgeneratetheskeletalelementsofthelimb,cellsfromthesomitesprovidethelimb’smusculature第8頁(yè)/共43頁(yè)第9頁(yè)/共43頁(yè)FGF10secretedfromthelateralplatemesodermcellsisthesignalforlimbbudinductionA:FGF10becomesexpressedinthelateralplatemesoderm

ofthelimbbud-formingregionB:EctopicexpressionofFGF10beneaththeflankectoderminducesextralimbFGF10Ectopiclimb第10頁(yè)/共43頁(yè)FGF10initiatesthelimbbud-forminginteractionsbetweentheectodermandthemesodermviadualsignalinginductionA:FGF10isoriginallyexpressedthroughoutthelateralplatemesodermB:FGF10becomesrestrictedtothelimbbud-formingregions,controlledbyWnt2bandWnt8crespectivelyC:DualinductionbetweenFGF10inthemesodermandFGF8intheapicalectodermridge(AER)Molecular

modelfortheinitiationofthelimbbudinthechickbetween48and54hoursofgestation第11頁(yè)/共43頁(yè)3Thelimbdevelopment3.1Specificationandformationofthelimbbud3.2Thelimboutgrowthandgenerationoftheproximal-distalaxis3.3Theanterior-posterioraxialpatterning3.4Patterningthedorsal-ventralaxis3.5Coordinatingthethreeaxes3.6DevelopmentofthedigitsDevelopmentofthevertebratelimb第12頁(yè)/共43頁(yè)第13頁(yè)/共43頁(yè)Apicalectodermalridge(AER)Progresszone(PZ)第14頁(yè)/共43頁(yè)TheAERisrequiredforboththeoutgrowthoflimbandthecorrectproximo-distalpatterning第15頁(yè)/共43頁(yè)FGF8isexpressedintheapicalectodermalridge(AER)第16頁(yè)/共43頁(yè)FGF8canfunctionallysubstitutefortheAERThesimilarresultscanbeobtainedwithFGF4,indicatingthatFGF8/FGF4arekeysignalsfortheAER第17頁(yè)/共43頁(yè)Themesenchymecells:

induceandsustaintheAER,anddeterminethetypeoflimbtobeformed.TheAER:

amajorsignalingcenterforthedevelopinglimb,andmaintainsthemesenchymeinaproliferatingphasethatenablesthePr-DgrowthofthelimbTheproximal-distalgrowthofthelimbbudinvolvesinteractionsbetweentheAERandtheunderlyingmesenchyme第18頁(yè)/共43頁(yè)

RoleoftheAERorthePZ(progresszone)inspecifyingtheproximal-distalaxis?

ThemechamismsunderlyingthePDaxisspecificationandpatterning?Howisdevelopmentoftheproximal-distalaxisaccomplishedduringthelimboutgrowth?第19頁(yè)/共43頁(yè)Specificationofproximal-distalaxisiscontrolledbytheprogresszonemesenchyme,rathertheAER(I)OlderAERcombinedwithyoungermesodermgeneratesnormallimbs,ratherproducinglimbswithdeletionsinthemiddle.YoungerAERcombinedwitholdermesodermgeneratesnormallimbs,ratherproducingduplicationsofstructures.ThefollowingtwotransplantationexperimentsdidnotsupportthenotionthattheAERspecifiestheproxiomal-distalaxisofthedevelopinglimbs.第20頁(yè)/共43頁(yè)Anearlywing-budprogresszonewastransplantedtoalatewingbudthathadalrealyformedulnaandradiusAlatewing-budprogresszonewastransplantedtoanearlywingbudExtraproximalstructureLackofintermediatestructuresSpecificationofproximal-distalaxisiscontrolledbytheprogresszonemesenchyme,rathertheAER(II)第21頁(yè)/共43頁(yè)TwoproposedmodelsforthemesodermalspecificationofthePr-Daxisofthelimb

a:thetimingmechanism,thecellfate

beingdeterminedbyhowlong

theyremainintheprogresszoneb:predeterminationinearlybud第22頁(yè)/共43頁(yè)HoxgenesspecifythePr-Daxisofthelimb第23頁(yè)/共43頁(yè)HoxgenesspecifythePr-DaxisofthelimbLossoffunctionmutationsinHoxa-11andHoxd-11

leadtolackingtheulnaandradiusoftheforelimbs

Humansynpolydactyly(manyfingersjoinedtogether)syndromeresultsfromhomozygosityforamutationattheHoxd-13loci第24頁(yè)/共43頁(yè)3Thelimbdevelopment3.1Specificationandformationofthelimbbud3.2Thelimboutgrowthandgenerationoftheproximal-distalaxis3.3Theanterior-posterioraxialpatterning3.4Patterningthedorsal-ventralaxis3.5Coordinatingthethreeaxes3.6Developmentofthedigits

Developmentofthevertebratelimb第25頁(yè)/共43頁(yè)Zoneofpolarizingactivity(ZPA)canspecifythelimbpatternalongtheanterior-posterioraxisThezoneofpolarizingactivity(ZPA)intheposteriorlimbbudhasorganizingpropertiesthatarealmostasstrikingasthoseoftheSpemannorganizerinamphibians第26頁(yè)/共43頁(yè)Sonichedgehog(Shh)isexpressedintheZPAShhShh第27頁(yè)/共43頁(yè)SonichedgehogdefinesthesignalingactivityoftheZPAfordevelopmentoftheAPaxis第28頁(yè)/共43頁(yè)ThemolecularbasisforspecificationofZPAFGF8intheAERinducesthemesenchymeexpressingthetranscriptionfactorsHoxb-8anddHANDtoexpressShh,therebyformingtheZPAintheposteriorregionoflimbbud第29頁(yè)/共43頁(yè)Sonichedgehogformsamorphogengradientthatspecifiespatternalongthelimb’santerior-posterioraxis第30頁(yè)/共43頁(yè)3Thelimbdevelopment3.1Specificationandformationofthelimbbud3.2Thelimboutgrowthandgenerationoftheproximal-distalaxis3.3Theanterior-posterioraxialpatterning3.4Patterningthedorsal-ventralaxis3.5Coordinatingthethreeaxes3.6Developmentofthedigits

Developmentofthevertebratelimb第31頁(yè)/共43頁(yè)Thedorsal-ventralpolarityofthelimbbudisdeterminedbytheectodermencasingit

Iftheectodermisrotated180withrespecttothelimbbudmesenchyme,thedorsal-ventralaxisispartiallyreversed.

TheWnt7ageneisspecificallyexpressedinthedorsal(butnotventral)ectodermofchickandmouselimbbuds,suggestingaroleofWnt7ainspecifyingdorsal-ventralpolarity.第32頁(yè)/共43頁(yè)LossofWnt7afunctionleadstodisruptionofthedorsal-ventralpatterningofthelimbVt:theventraltendons（肌腱）Vp:theventralfootpad（腳墊））A:WildtypeembryonicmouseforelimbpawB:ThemicedeficientforWnt7agene第33頁(yè)/共43頁(yè)ThemolecularmechanismsunderlyingtheWnt7a-mediatedDVpatterningofthelimbWnt7ainducesactivationoftheLmx1geneinthedorsalmesenchyme.Lmx1gene

encodesatranscriptionfactorthatappearstobeessentialforspecifyingdorsalcellfatesinthelimbSpatialexpressionofWnt7ainthedorsalectodermisregulatedbyengrailedgeneintheventralectoderm.第34頁(yè)/共43頁(yè)3Thelimbdevelopment3.1Specificationandformationofthelimbbud3.2Thelimboutgrowthandgenerationoftheproximal-distalaxis3.3Theanterior-posterioraxialpatterning3.4Patterningthedorsal-ventralaxis3.5Coordinatingthethreeaxes3.6DevelopmentofthedigitsDevelopmentofthevertebratelimb第35頁(yè)/共43頁(yè)Molecularinteractionsthatcoordinatelimbgrowthandpatterningalongthethreelimbaxes

第36頁(yè)/共43頁(yè)3Thelimbdevelopment3.1Specificatio