Ectodermal FGFs Induce Perinodular Inhibition of Limb Chondrogenesis in Vitro and in Vivo via FGF Receptor 2

[摘要] Theformationofcartilageelementsinthedevelopingvertebratelimb,wheretheyserveasprimordiafortheappendicularskeleton,isprecededbytheappearanceofdiscretecellularcondensations.Controlofthesizeandspacingofthesecondensationsisakeyaspectofskeletalpatternformation.Limbbudcellculturesgrownintheabsenceofectodermformedcontinuoussheet-likemassesofcartilage.Withtheinclusionofectoderm,theseculturesproducedoneormorecartilagenodulessurroundedbyzonesofnoncartilaginousmesenchyme.Ectodermalfibroblastgrowthfactors(FGF2andFGF8),butnotamesodermalFGF(FGF7),substitutedforectodermininhibitingchondrogenicgeneexpression,withsomecombinationsofthetwoectodermalfactorsleadingtowell-spacedcartilagenodulesofrelativelyuniformsize.TreatmentofcultureswithSU5402,aninhibitorFGFreceptortyrosinekinaseactivity,renderedFGFsineffectiveininducingperinodularinhibition.InhibitionofproductionofFGFreceptor2(FGFR2)bytransfectionofwingandlegcellcultureswithantisenseoligodeoxynucleotidesblockedappearanceofectoderm-orFGF-inducedzonesofperinodularinhibitionofchondrogenesisand,whenintroducedintothelimbbudsofdevelopingembryos,ledtoshorter,thicker,andfusedcartilageelements.BecauseFGFR2isexpressedmainlyatsitesofprecartilagecondensationduringlimbdevelopmentinvivoandinvitro,theseresultssuggestthatactivationofFGFR2byFGFsduringdevelopmentelicitsalateralinhibitorofchondrogenesisthatlimitstheexpansionofdevelopingskeletalelements.

[学科分类] 生物科学（综合）

[关键词] limb development;pattern formation;fibroblast growth factor;FGF receptor;lateral inhibition