VI 胚层发育与器官系统发生(II)

VI胚层发育与器官系统发生(II)TheembryonicchickwingThevertebratelimbdevelopmentisaparticularlygoodsysteminwhichtostudypatternformationduringorganogenesis(I)Thevertebratelimbisacomplexorganwiththreedevelopmentalaxes:theproximo-distalaxisrunningfromthebaseofthelimbtothetip,theantero-posterioraxisrunningparallelwiththebodyAPaxis,andthedorso-ventralaxisrunningfromthebackofthehandtothepalm.Thus,thelimbdevelopmentisaparticularlygoodsysteminwhichtostudypatternformationSincethelimbs,unlikeheartorbrain,arenotessentialforembryoniclife,onecanexperimentallyremoveortransplantpartsofthedevelopinglimb,orcreatelimb-specificmutantswithoutinterferingwiththevitalprocessesoftheorganism.ThisisgoodadvantageofstudyingpatternformationinorganogenesisThevertebratelimbdevelopmentisaparticularlygoodsysteminwhichtostudypatternformationduringorganogenesis(II)Thelimbisagoodmodelforstudyingcellularinteractionswithinastructurecontainingalargenumberofcells,andforelucidatingtheroleofintercellularsignalingindevelopment.Recently,particularsignalproteinshavebeenidentifiedtofunctioninpatterningalongeachofthreelimbaxes:FGFfamilyinPr-DaxialpatterningSonichedgehog(Shh)proteininA-PaxialpatterningWnt7ainD-VaxialpatterningThevertebratelimbdevelopsfromalimbbud3Thelimbdevelopment3.1Specificationandformationofthelimbbud3.2Thelimboutgrowthandgenerationoftheproximal-distalaxis3.3Theanterior-posterioraxialpatterning3.4Patterningthedorsal-ventralaxis3.5Coordinatingthethreeaxes3.6DevelopmentofthedigitsDevelopmentofthevertebratelimb3Thelimbdevelopment3.1Specificationandformationofthelimbbud3.2Thelimboutgrowthandgenerationoftheproximal-distalaxis3.3Theanterior-posterioraxialpatterning3.4Patterningthedorsal-ventralaxis3.5Coordinatingthethreeaxes3.6DevelopmentofthedigitsDevelopmentofthevertebratelimbThevertebratelimbdevelopsfromalimbbudProliferationofmesodermalcellsfromthelateralplatemesodermcausesthelimbbudtobulgeoutwardWhilethelateralplatemesodermalcellsgeneratetheskeletalelementsofthelimb,cellsfromthesomitesprovidethelimb’smusculatureFGF10secretedfromthelateralplatemesodermcellsisthesignalforlimbbudinductionA:FGF10becomesexpressedinthelateralplatemesodermofthelimbbud-formingregionB:EctopicexpressionofFGF10beneaththeflankectoderminducesextralimbFGF10EctopiclimbFGF10initiatesthelimbbud-forminginteractionsbetweentheectodermandthemesodermviadualsignalinginductionA:FGF10isoriginallyexpressedthroughoutthelateralplatemesodermB:FGF10becomesrestrictedtothelimbbud-formingregions,controlledbyWnt2bandWnt8crespectivelyC:DualinductionbetweenFGF10inthemesodermandFGF8intheapicalectodermridge(AER)Molecularmodelfortheinitiationofthelimbbudinthechickbetween48and54hoursofgestation3Thelimbdevelopment3.1Specificationandformationofthelimbbud3.2Thelimboutgrowthandgenerationoftheproximal-distalaxis3.3Theanterior-posterioraxialpatterning3.4Patterningthedorsal-ventralaxis3.5Coordinatingthethreeaxes3.6DevelopmentofthedigitsDevelopmentofthevertebratelimbFGF8isexpressedintheapicalectodermalridge(AER)FGF8canfunctionallysubstitutefortheAERThesimilarresultscanbeobtainedwithFGF4,indicatingthatFGF8/FGF4arekeysignalsfortheAERThemesenchymecells:induceandsustaintheAER,anddeterminethetypeoflimbtobeformed.TheAER:amajorsignalingcenterforthedevelopinglimb,andmaintainsthemesenchymeinaproliferatingphasethatenablesthePr-DgrowthofthelimbTheproximal-distalgrowthofthelimbbudinvolvesinteractionsbetweentheAERandtheunderlyingmesenchymeRoleoftheAERorthePZ(progresszone)inspecifyingtheproximal-distalaxis?ThemechamismsunderlyingthePDaxisspecificationandpatterning?Howisdevelopmentoftheproximal-distalaxisaccomplishedduringthelimboutgrowth?Specificationofproximal-distalaxisiscontrolledbytheprogresszonemesenchyme,rathertheAER(I)OlderAERcombinedwithyoungermesodermgeneratesnormallimbs,ratherproducinglimbswithdeletionsinthemiddle.YoungerAERcombinedwitholdermesodermgeneratesnormallimbs,ratherproducingduplicationsofstructures.ThefollowingtwotransplantationexperimentsdidnotsupportthenotionthattheAERspecifiestheproxiomal-distalaxisofthedevelopinglimbs.Anearlywing-budprogresszonewastransplantedtoalatewingbudthathadalrealyformedulnaandradiusAlatewing-budprogresszonewastransplantedtoanearlywingbudExtraproximalstructureLackofintermediatestructuresSpecificationofproximal-distalaxisiscontrolledbytheprogresszonemesenchyme,rathertheAER(II)TwoproposedmodelsforthemesodermalspecificationofthePr-Daxisofthelimba:thetimingmechanism,thecellfatebeingdeterminedbyhowlongtheyremainintheprogresszoneb:predeterminationinearlybudHoxgenesspecifythePr-DaxisofthelimbHoxgenesspecifythePr-DaxisofthelimbLossoffunctionmutationsinHoxa-11andHoxd-11leadtolackingtheulnaandradiusoftheforelimbsHumansynpolydactyly(manyfingersjoinedtogether)syndromeresultsfromhomozygosityforamutationattheHoxd-13loci3Thelimbdevelopment3.1Specificationandformationofthelimbbud3.2Thelimboutgrowthandgenerationoftheproximal-distalaxis3.3Theanterior-posterioraxialpatterning3.4Patterningthedorsal-ventralaxis3.5Coordinatingthethreeaxes3.6DevelopmentofthedigitsDevelopmentofthevertebratelimbZoneofpolarizingactivity(ZPA)canspecifythelimbpatternalongtheanterior-posterioraxisThezoneofpolarizingactivity(ZPA)intheposteriorlimbbudhasorganizingpropertiesthatarealmostasstrikingasthoseoftheSpemannorganizerinamphibiansSonichedgehog(Shh)isexpressedintheZPAShhShhSonichedgehogdefinesthesignalingactivityoftheZPAfordevelopmentoftheAPaxisThemolecularbasisforspecificationofZPAFGF8intheAERinducesthemesenchymeexpressingthetranscriptionfactorsHoxb-8anddHANDtoexpressShh,therebyformingtheZPAintheposteriorregionoflimbbudSonichedgehogformsamorphogengradientthatspecifiespatternalongthelimb’santerior-posterioraxis3Thelimbdevelopment3.1Specificationandformationofthelimbbud3.2Thelimboutgrowthandgenerationoftheproximal-distalaxis3.3Theanterior-posterioraxialpatterning3.4Patterningthedorsal-ventralaxis3.5Coordinatingthethreeaxes3.6DevelopmentofthedigitsDevelopmentofthevertebratelimbThedorsal-ventralpolarityofthelimbbudisdeterminedbytheectodermencasingitIftheectodermisrotated180withrespecttothelimbbudmesenchyme,thedorsal-ventralaxisispartiallyreversed.TheWnt7ageneisspecificallyexpressedinthedorsal(butnotventral)ectodermofchickandmouselimbbuds,suggestingaroleofWnt7ainspecifyingdorsal-ventralpolarity.LossofWnt7afunctionleadstodisruptionofthedorsal-ventralpatterningofthelimbVt:theventraltendons（肌腱）Vp:theventralfootpad（脚垫））A:WildtypeembryonicmouseforelimbpawB:ThemicedeficientforWnt7ageneThemolecularmechanismsunderlyingtheWnt7a-mediatedDVpatterningofthelimbWnt7ainducesactivationoftheLmx1geneinthedorsalmesenchyme.Lmx1geneencodesatranscriptionfactorthatappearstobeessentialforspecifyingdorsalcellfatesinthelimbSpatialexpressionofWnt7ainthedorsalectodermisregulatedbyengrailedgeneintheventralectoderm.3Thelimbdevelopment3.1Specificationandformationofthelimbbud3.2Thelimboutgrowthandgenerationoftheproximal-distalaxis3.3Theanterior-posterioraxialpatterning3.4Patterningthedorsal-ventralaxis3.5Coordinatingthethreeaxes3.6DevelopmentofthedigitsDevelopmentofthevertebratelimbMolecularinteractionsthatcoordinatelimbgrowthandpatterningalongthethreelimbaxes3Thelimbdevelopment3.1Specificationandformationofthelimbbud3.2Thelimboutgrowthandgenerationoftheproximal-distalaxis3.3Theanterior-posterioraxialpatterning3.4Patterningthedorsal-ventralaxis3.5Coordinatingthethreeaxes3.6DevelopmentofthedigitsDevelopmentofthevertebratelimbTheinterdigitaltissuespecifiestheidentityofthedigitforminganteriorlytotheinterdigitalregioninchickfeetThedigitalidentityisregulatedbyBMPsignalingintheinterdigitalregionApplicationoftheBMPinhibitorNoggintotheinterdigitalregionscausesalterationsinthedigitalidentitysimilartothoseobservedwhentheinterdigitalregionisremovedSeparationofthedigitsistheresultofprogrammedcelldeathRegulationofthelimbapoptosisbyBMPsGremlin:aninhibitorofBMPsInhibitionofcelldeathintheinterdigitalregionsbyblockingBMPsignalingleadstothewebbingofchickfeet