Ephrin-B2 governs morphogenesis of endolymphatic sac and duct epithelia in the mouse inner ear

摘要

Controloverioniccompositionandvolumeoftheinnerearluminalfluidendolymphisessentialfornormalhearingandbalance.MicedeficientineithertheEphB2receptortyrosinekinaseorthecognatetransmembraneligandephrin-B2(Efnb2)exhibitbackgroundstrain-specificvestibular-behavioraldysfunctionandsignsofabnormalendolymphhomeostasis.Usingvariousloss-of-functionmousemodels,wefoundthatemEfnb2/emisrequiredforgrowthandmorphogenesisoftheembryonicendolymphaticepithelium,aprecursoroftheendolymphaticsac(ES)andduct(ED),whichmediateendolymphhomeostasis.ConditionalinactivationofemEfnb2/eminearly-stageembryoniceartissuesdisruptedcellproliferation,cellsurvival,andepithelialfoldingattheoriginoftheendolymphaticepithelium.ThiscorrelatedwithapparentabsenceofanED,mis-localizationofESiontransportcellsrelativetoinnerearsensoryorgans,dysplasiaoftheendolymphfluidspace,andabnormallyformedotoconia(extracellularcalcite-proteincomposites)atlaterstagesofembryonicdevelopment.AcomparisonofEfnb2andNotchsignaling-deficientmutantphenotypesindicatedthatthesetwosignalingsystemshavedistinctandnon-overlappingrolesinES/EDdevelopment.HomozygousdeletionoftheEfnb2C-terminuscausedabnormalitiessimilartothosefoundintheconditionalemEfnb2/emnullhomozygote.AnalysesoffetalEfnb2C-terminusdeletionheterozygotesfoundmis-localizedESiontransportcellsonlyinthegeneticbackgroundexhibitingvestibulardysfunction.Weproposethatdevelopmentaldysplasiasdescribedhereareagenedose-sensitivecauseofthevestibulardysfunctionobservedinEphBndash;Efnb2signaling-deficientmice./p/div