(发育生物学）VI 胚层发育与器官系统发生(I)

(发育生物学）VI胚层发育与器官系统发生(I)MajorderivativesoftheectodermgermlayerdorsalventralMajorderivativesofthemesodermgermlayerThemajorfunctionoftheembryonicendodermistoconstructtheliningsoftwotubeswithinthevertebratebodyThedigestivetubeanditsderivatives(liver,gallbladder,andpancreas)ThemajorfunctionoftheembryonicendodermistoconstructtheliningsoftwotubeswithinthevertebratebodyTherespiratorytubeThedigestivetubeanditsderivatives(liver,gallbladder,andpancreas)Developmentofthegermlayersandorganogenesis1Developmentofthegermlayers1.1Ectoderm1.2Paraxialandintermediatemesoderm1.3Lateralplatemesodermandendoderm2Developmentofthenervoussystem2.1Thespecificationofneuralcell(neuronorglialcell)identity2.2Migrationofneuronsandtheguidedoutgrowthofaxonstowardtheirtargetcells2.3SynapseformationandrefinementDevelopmentofthenervoussystemThenervoussystemisthemostcomplexofalltheorgansystemsintheanimalembryo.Inmammals,forexample,billionsofnervecells,orneurons,developahighlyorganizedpatternofconnections,creatingtheneuronalnetworkthatmakesupthefunctioningbrainandtherestofthenervoussystem.Thenervoussystemcontainsmanyhundredsofdifferenttypesofneurons,varyinginsizes,shapesandfunctions.Thenervoussystemcanonlyfunctionproperlyiftheneuronsarecorrectlyconnectedtooneanother,thusacentralquestioninnervoussystemdevelopmentishowtheconnectionsbetweenneuronswitheachotherandwithothertargetcellsdevelopwiththeappropriatespecificity.DevelopmentofthenervoussystemNeuronsconnectwitheachotherandwithothertargetcells,suchasmuscle,atspecilizedjunctionsknownassynapses（突触）.Aneuronreceivesinputfromotherneuronsthroughitshighlybrancheddendrites,andgenerateanerveimpulseatthecellbody.Thisnerveimpulseisthenconductedalongtheaxontotheaxonterminal,whichmakesasynapsewiththedendritesorcellbodyofanotherneuronorwiththesurfaceofamusclecell.Thedendritesandaxonterminalsofindividualneuronscanbeextensivelybranched,andasingleneuronintheCNScanreceiveasmanyas100,000differentinput.DevelopmentofthenervoussystemDevelopmentofthenervoussysteminvolveneuronalcelldifferentiation,migration,andmorphogenesisTheoverallprocessofnervous-systemdevelopmentcanbedividedupintofourmajorstages:Thespecificationofneuralcellidentity(neuronorglialcell)ThemigrationofneuronsandtheoutgrowthofaxonstotheirtargetsTheformationofsynapsesbetweenneuronswitheachotherandwithothertargets,suchasmuscleetcTherefinementofsynapticconnectionsthroughtheeliminationofaxonbranchesandcelldeathDevelopmentofthegermlayersandorganogenesis1Developmentofthegermlayers1.1Ectoderm1.2Paraxialandintermediatemesoderm1.3Lateralplatemesodermandendoderm2Developmentofthenervoussystem2.1Thespecificationofneuralcellidentity(neuronorglialcell)2.2Migrationofneuronsandtheguidedoutgrowthofaxonstowardtheirtargetcells2.3SynapseformationandrefinementDevelopmentofthegermlayersandorganogenesis1Developmentofthegermlayers1.1Ectoderm1.2Paraxialandintermediatemesoderm1.3Lateralplatemesodermandendoderm2Developmentofthenervoussystem2.1Thespecificationofneuralcellidentity(neuronorglialcell)2.2Migrationofneuronsandtheguidedoutgrowthofaxonstowardtheirtargetcells2.3SynapseformationandrefinementThepresumptivenervoussystemisspecifiedearlyinembryonicdevelopmentinbothinvertebratesandvertebratesThepresumptivenervoussystemisspecifiedearlyinembryonicdevelopmentinbothinvertebratesandvertebratesNeuroepitheliumatthedorsalmidlineSpecificationoftheneuronalprecursorsinvolveslateralinhibitioninbothinvertebratesandvertebratesInDrosophila,theneurectodermissubdividedalongtheAPandDVaxesintoapreciseorthogonal（直角）patternofproneuralclusters(原神经簇)Withineachproneuralcluster,cell-cellinteractionsthroughNotchsignaling–mediatedlateralinhibitiondirectonecellintoaneuronalprecursororneuroblastfate.Therestbecomeepidermalcells.SpecificationoftheneuronalprecursorsinvolveslateralinhibitioninbothinvertebratesandvertebratesInDrosophila,theneurectodermissubdividedalongtheAPandDVaxesintoapreciseorthogonal（直角）patternofproneuralclusters.Withineachcluster,cell-cellinteractionsthroughNotchsignaling–mediatedlateralinhibitiondirectonecellintoaneuronalprecursororneuroblastfate.Therestbecomeepidermalcells.AsinDrosophila,lateralinhibitionspecifiessinglecellsasneuronalprecursorsinthevertebratenervoussystem.Thecellfatedeterminantsforneuronalprecursors/neuroblast:Achaete-ScutecomplexFurtherdevelopmentofneuronsfromneuronalprecursorsinvolvesasymmetriccelldivisioninDrosophilaAfterspecification,theDrosophilaneuroblastsdelaminatefromtheneurectodermalepitheliumtolieadjacenttoitsinner,orbasalface,andthenbehaveasastemcells.Eachneuroblastdividesasymmetricallytogiveanapicalcell,whichremainsaneuralstemcell,andasmallerbasalcell,theganglionmothercell(GMCs神经节母细胞),whichwilldifferentiateintoneurons.Thelocalizedproteindeterminantsinneuroblastsspecifydaughtercellfateandtheorientationofcelldivision(ensuringtheasymmetricdistributionofthecellfatedetermiants):Numb:theganglionmothercellfatedeterminantInsc/Pins:theorientationoftheplaneofcelldivisionThepatternofdifferentiationofcellsalongtheDVaxisofthespinalcorddependsonventralanddorsalsignalsThereisadistinctdorso-ventralpatterninthedevelopingspinalcordofvertebrates.Specifically,differenttypesofneuronsdifferentiatealongtheDVaxis.Motorneuronsandinterneuronsarelocatedventrally,whereascommissuralneurons（连合神经元）differentiateinthedorsalregionDifferentiationofneuronalsubtypesalongtheDVaxisisdeterminedbySonichedgehogprotein(Shh),theventralsignalsecretedbythenotochord,andBMPs,thedorsalsignalfromthedorsalepidermalectodermBMPsignalShhsignalThegradientsoftwosignalproteinsdeterminetheneuronidentityalongtheDVaxisofthespinalcordThegradedsignalproteinscausedifferenttranscriptionfactorstobeactivatedinthenucleioftheneuronalcells,dependingontheirpositionalongtheDVaxisAgradedSonichedgehogsignalpatternsdifferentneuronaltypesintheventralregionofthespinalcordthroughregulatingtwoclassesofhomeodomainproteingenesNkx6.1Nkx2.2Developmentofthegermlayersandorganogenesis1Developmentofthegermlayers1.1Ectoderm1.2Paraxialandintermediatemesoderm1.3Lateralplatemesodermandendoderm2Developmentofthenervoussystem2.1Thespecificationofneuralcellidentity(neuronorglialcell)2.2Migrationofneuronsandtheguidedoutgrowthofaxonstowardtheirpartner/targetcells2.3SynapseformationandrefinementThedevelopmentalprocessforestablishingthefunctioningneuronalnetworkMigrationofimmatureneuronsThemigrationofneuralcrestcellsWhatcontrolstheneuralcrestmigration?Outgrowthofaxonstowardtheirpartner/targets(axonguidance)Howisthegrowthofaxonsguided?Whatarethemechanismsunderlyingtheaxonguidance?Thefunctioningneuronalnetworkinvolvesbothmigrationofimmatureneuronsandoutgrowthofaxonstowardtheirpartner/targetsMigrationofneuralcrestcellsandaxonaloutgrowthofneuronssharethepropertyofhavingtomigratefarfromtheirsourceoforigintospecificplacesintheembryoTheybothneedtorecognizecues(信号)tobeginthismigration,andrespondtosignalsthatguidethemalongspecificroutestotheirfinaldestinationManyofthesignalsrecognizedbyneuralcrestcellsandbythegrowingaxonsofneuronsarethesameThefunctioningneuronalnetworkinvolvesbothmigrationofimmatureneuronsandoutgrowthofaxonstowardtheirtargets(I)Thefunctioningneuronalnetworkinvolvesbothmigrationofimmatureneuronsandoutgrowthofaxonstowardtheirtargets(I)MigrationofimmatureneuronsThemigrationofneuralcrestcellsWhatcontrolsthetheneuralcrestmigration?Outgrowthofaxonstowardtheirtargets(axonguidance)Howisthegrowthofaxonsguided?Whatarethemechanismsunderlyingtheaxonguidance?NeuroepitheliumatthedorsalmidlinedorsalventralNeuralcrestcellsmigrateextensivelytogeneratealargenumberofdifferentiatedcelltypesThefateoftheneuralcrestcellsdepends,toalargedegree,onwheretheymigratetoandsettleTheneuralcrestcanbedividedinto4maindomains(overlapping),eachwithcharacteristicderivativesandfunctionsThecranial(cephalic头部)neuralcrestcells：Thecartilage,bone,cranialneurons,gliaandconnectivetissuesofthefaceThetrunkneuralcrestcellsThedorsalrootgangliacontainingthesensoryneuronsThesympatheticganglia,theadrenalmedulla,melanocytesetcThevagal(neck)andsacral(骶)neuralcrestcellsParasympatheticgangliaofthegutThecardiacneuralcrestcellsMelanocytes,neurons,cartilage,andconnectivetissuesTheentiremuscular-connectivetissuewallofthelargearteriesNeuralcrestcellmigrationiscontrolledbyenvironmentalcuesandadhensivedifferences(I)TheadhensivedifferencesThedynamicexpressionofN-cadherininneuralcrestcellsisessentialfortheinitiationofneuralcrestcells,thesegregationoftheneuralcrestcellsfromtheneuraltube.(N-cadherinisexpressedinneuralcrestcellspriortomigration,andaftermigration.But,down-regulationofN-cadherinexpressionatthetimeofmigration,andturningoffofN-cadherinexpressionduringmigration)ConstitutiveexpressionofN-cadherindramaticallysupressesthemovementoftheneuralcrestcellsfromtheneuraltube.Neuralcrestcellmigrationiscontrolledbyenvironmentalcuesandadhensivedifferences(I)TheadhensivedifferencesThedynamicexpressionofN-cadherininneuralcrestcellsisessentialfortheinitiationofneuralcrestcells,thesegregationoftheneuralcrestcellsfromtheneuraltube.(N-cadherinisexpressedinneuralcrestcellspriortomigration,andaftermigration.But,down-regulationofN-cadherinexpressionatthetimeofmigration,andturningoffofN-cadherinexpressionduringmigration)ConstitutiveexpressionofN-cadherindramaticallysupressesthemovementoftheneuralcrestcellsfromtheneuraltube.Question???WhataretheregulatorymechansimsunderlyingthedynamicexpressionofN-cadherinduringtheprocess?Neuralcrestcellmigrationiscontrolledbyenvironmentalcuesandadhensivedifferences(II)Theenvironmentalcues(cuesfromtheextracellularmatrices)Migration-promotingproteins:ManydifferentextracellularmatrixmoleculeshavebeendetectedalongneuralcrestmigratorypathwaysFibronectin(纤维连接蛋白)Laminin(层粘连蛋白)CollagenmoleculesProteoglycansetc(bybindingtointegrininneuralcrestcellsurface)Migration-impedingproteins:Ephrinproteins(bybindingtoEphreceptorinneuralcrestcellmembranes)Thefunctioningneuronalnetworkinvolvesbothmigrationofimmatureneuronsandoutgrowthofaxonstowardtheirtargets(II)MigrationofimmatureneuronsThemigrationofneuralcrestcellsWhatcontrolsthetheneuralcrestmigration?Outgrowthofaxonstowardtheirpartner/targets(axonguidance)Howistheoutgrowthofaxonsguided?Whatarethemechanismsunderlyingtheaxonguidance?ThegrowthconecontrolsthepathtakenbythegrowingaxonDendritesarethefine,branchingextensionsoftheneuronthatareusedtopickupelectricimpulsesfromothercells.Inhuman,theaveragecorticalneuronconnectswith10,000otherneuralcells.Axonisacontinuousextensionofthenervecellbodywhichmaybeseveralfeetlong.Neuronsmakefunctionalconnectionswiththeirpartner/targetsthroughoutgrowthofaxons.Theoutgrowthoftheaxonisguidedbythegrowthcone(生长锥)attheaxontipThegrowthconemovesbytheelongationandcontractionofpointedfilopodiacalledmicrospikes(微突).Thesemicrospikescontainactinmicrofilaments,whichareorientedparalleltothelongaxisoftheaxon.ThegrowthconecontrolsthepathtakenbythegrowingaxonactintubulinThegrowthconebothmovesandsensesitsenvironment,functioningasbothlocomotorandsensoryapparatusIngeneral,thegrowthconemovesinthedirectioninwhichitsfilopodiamakethemoststablecontactswithothercellsandwiththeextracellularmatrix.Theextracellularsignalscanbindtoreceptorsonthegrowthconesurface,andinfluenceitsdirectionofmigration.Theextensionandretractionoffilopodiainvolvestheassemblyanddisassemblyoftheactincytoskeleton.Membersofafamilyofintracellularsignalingproteins,theRas-relatedGTPases,areinvolvedinthereorganizationoftheactincytoskeleton:ActivationofRhocausegrowthconestostopextendingRacandCdc42areinvolvedingrowth-coneextensionThegrowthconecontrolsthepathtakenbythegrowingaxonIngeneral,thegrowthconemovesinthedirectioninwhichitsfilopodiamakethemoststablecontactswithothercellsandwiththeextracellularmatrix.Theextracellularsignalscanbindtoreceptorsonthegrowthconesurface,andinfluenceitsdirectionofmigration.Theextensionandretractionoffilopodiainvolvestheassemblyanddisassemblyoftheactincytoskeleton.Membersofafamilyofintracellularsignalingproteins,theRas-relatedGTPases,areinvolvedinthereorganizationoftheactincytoskeleton:ActivationofRhocausegrowthconestostopextendingRacandCdc42areinvolvedingrowth-coneextensionHowgrowthconestransduceextracellularsignalssoastoextendorcollapsefilopodiaisnotfullyunderstood.ThegrowthconecontrolsthepathtakenbythegrowingaxonAxongrowthconesareguidedbytwomaintypesofcue—attractiveandrepulsivesignalsChemoattractantproteinsNetrinsCadherinsChemorepellantproteinsSemaphorinsEphrinSlitproteinsThesesignalproteinsoftenfunctionasbothattractantsandrepellants,dependingonthecellularcontextAxongrowthconesareguidedbytwomaintypesofcue-attractiveandrepulsiveNetrin-1isakeyattractantproducedinthefloorplateandinthemidlineDevelopmentofthegermlayersandorganogenesis1Developmentofthegermlayers1.1Ectoderm1.2Paraxialandintermediatemesoderm1.3Lateralplatemesodermandendoderm2Developmentofthenervoussystem2.1Thespecificationofneuralcell(neuronorglialcell)identity2.2Migrationofneuronsandtheguidedoutgrowthofaxonstowardtheirtargetcells2.3SynapseformationandrefinementSynapseformationandrefinement(I)Whenaxonsreachtheirpartner/targetstheyformspecializedjunctionscalledsynapses.NeurotransmittersfromtheaxonterminalarereleasedatthesesynapsestodepolarizeorhyperpolarizeofthemembraneofthetargetcellacrossthesynapticcleftNeuronscanmakeconnectionswithothernervecells,withmuscles,andalsowithcertainglandulartissues.Thevertebrateneuromuscularjunction(NMJ)betweenmotorneuronandmusclecellisabeststudiedsynapse,studiesofwhichsignificantlycontributetotheunderstandingofsynapseformationSynapseformationinvolvesreciprocalsignalinginteractionsbetweenneuronandmusclecell(NMJ)oraxonsanddendritesofneurons(Interneuronalsynapse)Keyevents:reciprocalsignalinginteractionsSynapseformationandrefinement(II)Thefunctioningofthenervoussystemdependsontheestablishmentofspecificsynapsesbetweenneuronsandtheirpartner/targets.Itmeansthatinitialsynapticconnectionsneedtoberefined.TherefinementiswellstudiedinsynapseformationoftheNMJ.Specificityofsynapsesappearstobeachievedby:Initialoverproductionofmotorneuronsthatcompetefortargets,resultingindeathofmanymotorneuronsduringdevelopment(duetolackingsurvivalfactorssuchasneurotrophicfactorsfromthetargets)Competitionexistsbetweeninitiallyestablishedsynapses,eliminatingmostofthosesynapticconnections(refinements).Developmentofthegermlayersandorganogenesis1Developmentofthegermlayers1.1Ectoderm1.2Paraxialandintermediatemesoderm1.3Lateralplatemesodermandendoderm2Developmentofthenervoussystem2.1Thespecificationofneuralcell(neuronorglialcell)identity2.2Migrationofneuronsandtheguidedoutgrowthofaxonstowardtheirtargetcells2.3Synapseformationandrefinement