Signaling Pathways Crucial for Craniofacial Development Revealed by Endothelin-A Receptor-Deficient Mice
[摘要] Mostoftheboneandcartilageinthecraniofacialregionisderivedfromcephalicneuralcrestcells,whichundergothreeprimarydevelopmentalevents:migrationfromtherhombomericneuroectodermtothepharyngealarches,proliferationastheectomesenchymewithinthearches,anddifferentiationintoterminalstructures.Interactionsbetweentheectomesenchymalcellsandsurroundingcellsarerequiredintheseprocesses,inwhichdefectscanleadtocraniofacialmalformation.WehavepreviouslyshownthattheG-protein-coupledendothelin-Areceptor(ETA)isexpressedintheneuralcrest-derivedectomesenchyme,whereasthecognateligandforETA,endothelin-1(ET-1),isexpressedinarchepitheliumandtheparaxialmesoderm-derivedarchcore;absenceofeitherETAorET-1resultsinnumerouscraniofacialdefects.InthisstudywehaveattemptedtodefinethepointatwhichcephalicneuralcrestdevelopmentisdisruptedinETA-deficientembryos.Wefindthat,whileneuralcrestcellmigrationintheheadofETAminus;/minus;embryosappearsnormal,expressionofanumberoftranscriptionfactorsinthearchectomesenchymalcellsiseitherabsentorsignificantlyreduced.TheseETA-dependentfactorsincludethetranscriptionfactorsgoosecoid,Dlx-2,Dlx-3,dHAND,eHAND,andBarx1,butnotMHox,Hoxa-2,CRABP1,orUfd1.Inaddition,thesizeofthearchesinE10.5toE11.5ETAminus;/minus;embryosissmallerandanincreaseinectomesenchymalapoptosisisobserved.Thus,ETAsignalinginectomesenchymalcellsappearstocoordinatespecificaspectsofarchdevelopmentbyinducingexpressionoftranscriptionfactorsinthepostmigratoryectomesenchyme.Absenceofthesesignalsresultsinretardedarchgrowth,defectsinproperdifferentiation,and,insomemesenchymalcells,apoptosis.Inparticular,thisdevelopmentalpathwayappearsdistinctfromthepathwaythatincludesUFD1L,implicatedasacausativegeneinCATCH22patients,andsuggestsparallelcomplementarypathwaysmediatingcraniofacialdevelopment.
