OMIMOnlineMendelianInheritanceinManAll DatabasesPubMedNucleotideProteinGenomeStructurePMCTaxonomyOMIM SearchPubMedProteinNucleotideCoreNucleotideGSSESTStructureGenomeBooksCancerChromosomesConservedDomainsdbGaP3DDomainsGeneGenomeProjectGENSATGEOProfilesGEODataSetsHomoloGeneJournalsMeSHNCBIWebSiteNLMCatalogOMIAOMIMPMCPopSetProbeProteinClustersPubChemBioAssayPubChemCompoundPubChemSubstanceSNPTaxonomyToolKitUniGeneUniSTSLimitsPreview/IndexHistoryClipboardDetailsDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardAll1OMIMdbSNP0OMIMUniSTS0*603687LinksALDEHYDEDEHYDROGENASE1FAMILYMEMBERA2ALDH1A2AlternativetitlessymbolsRETINALDEHYDEDEHYDROGENASE2RALDH2GenemaplocusChr15TEXTCLONINGRetinoicacid(RA)adevelopmentalsignalimplicatedintheformationoftheneuralaxisispresentathighlevelsintheearlyembryonictrunkregionincludingtheHensennodeRetinaldehydedehydrogenaseconvertsretinaldehydetoRAZhaoetal(1996)clonedacDNARaldh2frommouseP19teratocarcinomacellsthatencodedanNADdependentaldehydedehydrogenasewithhighsubstratespecificityforretinaldehydeThecDNAencodesa499aminoacidproteinwith70%similaritytoclass1aldehydedehydrogenasesTheproteincontainstheconservedmotifscharacteristicofotheraldehydedehydrogenasestheNADbindingdomaincontainingthemotifGXGXXXG2conservedpeptidemotifsandcys301whichisthecriticalresidueforinteractionwiththealdehydegroupTransfectioninCOS7cellsindicatedthatRaldh2effectivelycatalyzedthesynthesisofRAfromretinaldehydeRaldh2didnotoxidizeanyothersubstratetestedItspatternofexpressionduringmousedevelopmentsuggestedthatitmayberesponsibleforembryonicRAsynthesisWangetal(1996)clonedtheratRaldh2cDNAWhilestudyingtheeffectofTAL1(187040)andLMO(see186921)onTcellacutelymphocyticleukemia(TALL)Onoetal(1998)clonedthehumanRALDH2cDNAInnormalTcellsGATA3(131320)bindstotheGATAsiteintheRALDH2promoterbutdoesnotactivatetranscriptionWhenTAL1andLMOareectopicallyexpressedinTALLalargecomplexcontainingTAL1LMOandGATA3isformedontheGATAsiteintheRALDH2TpromotertoactivatetranscriptionfromadownstreaminitiatorTheprecisespecificationofleftrightasymmetryisanessentialprocessforpatterninginternalorgansinvertebratesInmouseembryonicdevelopmentthesymmetrybreakingprocessinleftrightdeterminationisinitiatedbyaleftwardextraembryonicfluidflowonthesurfaceoftheventralnodeTanakaetal(2005)showedthatfibroblastgrowthfactor(FGF)signalingtriggerssecretionofmembranesheathedobjects03to5micronsindiametertermed'nodalvesicularparcels'(NVPs)whichcarrySonichedgehog(Shh600725)andretinoicacidTheseNVPsaretransportedleftwardbythefluidflowandeventuallyfragmentclosetotheleftwalloftheventralnodeThesilencingeffectsofanFGFreceptor(176943)inhibitoronNVPsecretionandonadownstreamriseincalciumweresufficientlyreversedbyexogenousSonichedgehogpeptideorretinoicacidsuggestingthatFGFtriggeredsurfaceaccumulationofcargomorphogensmaybeessentialforlaunchingNVPsTanakaetal(2005)proposedthatNVPflowisamodeofextracellulartransportthatformsaleftrightgradientofmorphogensUsingtimelapseimagingTanakaetal(2005)foundthattheseNVPsweretransportedleftwardonceevery5to15secondsMAPPINGTheInternationalRadiationHybridMappingConsortiummappedtheRALDH2genetochromosome15(RH76097)ANIMALMODELNiederreitheretal(1999)generatedatargeteddisruptionofthemouseRaldh2geneandfoundthatRaldh2/embryoswhichdiedatmidgestationwithoutundergoingaxialrotationexhibitedshorteningalongtheanterioposterioraxisopenneuraltubeandabsentlimbbudsTheirheartsconsistedofasinglemedialdilatedcavityTheirfrontonasalregionsweretruncatedandtheirotocystswereseverelyreducedThesedefectsresultedfromablockofembryonicRAsynthesisasshownbythelackofactivityofRAresponsivetransgenesthealteredexpressionofanRAtargethomeoboxgene(Hoxa1142955)andthenearfullrescueofthemutantphenotypebymaternalRAadministrationThedataestablishedthatRAsynthesizedbythepostimplantationmammalianembryoisanessentialdevelopmentalhormonewhoselackleadstoearlyembryonicdeathRetinoicacidtheactivederivativeofvitaminA(retinol)isahormonalsignalingmoleculethatactsindevelopingandadulttissuesThecytochromep45026(CYP26A1602239)metabolizesretinoicacidintomorepolarhydroxylatedandoxidizedderivativesCyp26a1/mousefetuseshavelethalmorphogeneticphenotypesmimickingthosegeneratedbyexcessretinoicacidadministrationindicatingthathumanCYP26A1maybeessentialincontrollingretinoicacidlevelsduringdevelopmentIfthisistruethentheCyp26a1/phenotypecouldbe'rescued'underconditionsinwhichembryonicretinoicacidlevelsaredecreasedNiederreitheretal(2002)showedthatthesenullmiceareindeedphenotypicallyrescuedbyheterozygousdisruptionofthegeneencodingAldh1a2whichencodesaretinaldehydedehydrogenaseresponsibleforthesynthesisofretinoicacidduringearlyembryonicdevelopmentAldh1a2haploinsufficiencypreventedtheappearanceofspinabifidaandrescuedthedevelopmentofposteriorstructures(sacral/caudalvertebraehindguturogenitaltract)whilepartlypreventingcervicalvertebraltransformationsandhindbrainpatternalterationsinCyp26a1/miceThussomeofthesedoublemutantmicecouldreachadulthoodThisstudywasthefirstreportofamutationactingasadominantsuppressorofalethalmorphogeneticmutationinmammalsNiederreitheretal(2002)providedgeneticevidencethatALDH1A2andCYP26A1activitiesconcurrentlyestablishlocalembryonicretinoicacidlevelsthatmustbefinelytunedtoallowposteriororgandevelopmentandtopreventspinabifidaPerlmann(2002)referredtothisrelationshipinretinoicmetabolismas'abalancingact'Vermotetal(2003)generatedmicebearingahypomorphicalleleoftheRALDH2geneTheresultingmutantmicewhichdiedperinatallyexhibitedfeaturesofDiGeorgesyndrome(188400)withheartoutflowtractseptationdefectsandanomaliesoftheaorticarchderivedheadandneckarterieslaryngealtrachealcartilagedefectsandthyroid/parathyroidaplasiaorhypoplasiaAnalysisofRaldh2hypomorphembryosshowedselectivedefectsoftheposterior(thirdtosixth)branchialarchesincludingabsenceorhypoplasiaofthecorrespondingaorticarchesandpharyngealpouchesandlocaldownregulationofretinoicacidtargetedgenesThusadecreasedlevelofembryonicretinoicacid(throughgeneticand/ornutritionalcauses)couldrepresentamajormodifieroftheexpressivityofhuman22q11delassociatedDiGeorge/velocardiofacialsyndromesandifsevereenoughcouldonitsownleadtotheclinicalfeaturesoftheDiGeorgesyndromeKeeganetal(2005)presentedanewmechanismforregulatingthenumberofprogenitorcellsinorgandevelopmentbylimitingtheirdensitywithinacompetentregionUsingazebrafishmutationthatdisruptsfunctionofraldh2theydemonstratedthatretinoicacidsignalingrestrictedcardiacspecificationinthezebrafishembryoReductionofretinoicacidsignalingcausedformationofanexcessofcardiomyocytesviafatetransformationsthatincreasedcardiacprogenitordensitywithinamultipotentialzoneThusretinoicacidsignalingcreatesabalancebetweencardiacandnoncardiacidentitiestherebyrefiningthedimensionsofthecardiacprogenitorpoolVermotetal(2005)foundthatRaldh2nullmiceexhibitdelayedsomiteformationontherightsideAsymmetricsomiteformationcorrelatedwithaleftrightdesynchronizationofthesegmentationclockoscillationsVermotetal(2005)concludedthattheirdataimplicatedretinoicacidasanendogenoussignalthatmaintainsthebilateralsynchronyofmesodermsegmentationandthereforecontrolsbilateralsymmetryinvertebrateembryosKawakamietal(2005)characterizedacascadeoflateralityinformationinthezebrafishembryoandshowedthatblockingtheearlystepsofthiscascadebeforeitreachesthelateralplatemesodermusingamorpholinomodifiedantisenseoligonucleotideagainstRaldh2resultsinrandomleftrightasymmetricsomitogenesisTheyalsouncoveredamechanismmediatedbyretinoicacidsignalingthatiscrucialinbufferingtheinfluenceoftheflowoflateralityinformationontheleftrightprogressionofsomiteformationandthusinensuringbilaterallysymmetricsomitogenesisTheleftrightaxisinzebrafishembryosiscontrolledby2parallelmechanismsonethatdependsonhydrogen/potassiumATPaseactivityandactsveryearlyindevelopment(beforethestartofzygotictranscription)andasecondmechanismakintothenodalflowofmouseembryoswhichtakesplaceinKupffer'svesicleduringearlysomitogenesisanddependsontheexpressionofleftrightdynein(lrd603339)andfunctionalciliaVermotandPourquie(2005)reportedthatblockingtheproductionofretinoicacidinchickenembryoswithaninhibitorofRaldh2ledtoadesynchronizationofsomiteformationbetweenthe2embryonicsidesdemonstratedbyashortenedleftsegmentedregionThisdefectwaslinkedtoalossofcoordinationofthesegmentationclockoscillationsThelateralizationofthisdefectledtheauthorstoinvestigatetherelationbetweensomitogenesisandtheleftrightasymmetrymachineryinRAdeficientembryosReversalofthesitusinchickormouseembryoslackingretinoicacidresultedinareversalofthesomitogenesislateralitydefectVermotandPourquie(2005)concludedthatretinoicacidisimportantinbufferingthelateralizinginfluenceoftheleftrightmachinerythuspermittingsynchronizationofthedevelopmentofthe2embryonicsidesREFERENCES1KawakamiYRayaARayaRMRodriguezEstebanCIzpisuaBelmonteJCRetinoicacidsignallinglinksleftrightasymmetricpatterningandbilaterallysymmetricsomitogenesisinthezebrafishembryoNature4351651712005PubMedID158890822KeeganBRFeldmanJLBegemannGInghamPWYelonDRetinoicacidsignalingrestrictsthecardiacprogenitorpoolScience3072472492005PubMedID156535023NiederreitherKAbuAbedSSchuhbaurBPetkovichMChambonPDollePGeneticevidencethatoxidativederivativesofretinoicacidarenotinvolvedinretinoidsignalingduringmousedevelopmentNatureGenet3184882002PubMedID119537464NiederreitherKSubbarayanVDollePChambonPEmbryonicretinoicacidsynthesisisessentialforearlymousepostimplantationdevelopmentNatureGenet214444481999PubMedID101924005OnoYFukuharaNYoshieOTAL1andLIMonlyproteinssynergisticallyinduceretinaldehydedehydrogenase2expressioninTcellacutelymphoblasticleukemiabyactingascofactorsforGATA3MolecCellBiol18693969501998PubMedID98193826PerlmannTRetinoidmetabolismabalancingactNatureGenet31792002NoteErratumNatureGenet31221only2002PubMedID119537477TanakaYOkadaYHirokawaNFGFinducedvesicularreleaseofSonichedgehogandretinoicacidinleftwardnodalflowiscriticalforleftrightdeterminationNature4351721772005PubMedID158890838VermotJLlamasJGFraulobVNiederreitherKChambonPDollePRetinoicacidcontrolsthebilateralsymmetryofsomiteformationinthemouseembryoScience3085635662005PubMedID157314049VermotJNiederreitherKGarnierJMChambonPDollePDecreasedembryonicretinoicacidsynthesisresultsinaDiGeorgesyndromephenotypeinnewbornmiceProcNatAcadSci100176317682003PubMedID1256303610VermotJPourquieORetinoicacidcoordinatessomitogenesisandleftrightpatterninginvertebrateembryosNature4352152202005PubMedID1588909411WangXPenzesPNapoliJLCloningofacDNAencodinganaldehydedehydrogenaseanditsexpressioninEscherichiacolirecognitionofretinalassubstrateJBiolChem27116288162931996PubMedID866319812ZhaoDMcCafferyPIvinsKJNeveRLHoganPChinWWDragerUCMolecularidentificationofamajorretinoicacidsynthesizingenzymearetinaldehydespecificdehydrogenaseEuropJBiochem24015221996PubMedID8797830CONTRIBUTORSAdaHamoshupdated5/25/2005AdaHamoshupdated5/3/2005AdaHamoshupdated1/27/2005VictorAMcKusickupdated3/27/2003VictorAMcKusickupdated4/22/2002JoannaSAmbergerupdated4/2/2001CREATIONDATEAdaHamosh3/31/1999EDITHISTORYtkritzer6/2/2005tkritzer5/26/2005terry5/25/2005alopez5/4/2005terry5/3/2005wwang2/7/2005wwang2/2/2005terry1/27/2005terry3/18/2004cwells4/1/2003terry3/27/2003alopez6/6/2002alopez4/24/2002terry4/22/2002carol4/3/2001joanna4/2/2001alopez5/9/2000alopez4/1/1999alopez3/31/1999alopez3/31/1999Copyright©19662007JohnsHopkinsUniversityDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardDisclaimerWritetotheHelpDeskPrivacyPolicyNCBINLMNIH