Sonic hedgehog-patched Gli signaling in the developing rat prostate gland: lobe-specific suppression by neonatal estrogens reduces ductal growth and branching

摘要

Whileprostateglanddevelopmentisdependentonandrogens,otherhormonesincludingretinoidsandestrogenscaninfluencethisprocess.Briefexposuretohigh-doseestrogenduringtheneonatalperiodinratsleadstopermanent,lobe-specificaberrationsintheprostategland,aphenomenonreferredtoasdevelopmentalestrogenization.Wehavepreviouslyshownthatthisresponseismediatedthroughalterationsinsteroidreceptorexpression;however,furtherdownstreammechanismsremainunclear.Herein,weexaminedSonichedgehog(emShh/em)-patched(emptc/em)-emgli/eminthedevelopingratprostategland,itsroleinbranchingmorphogenesis,andtheeffectsofneonatalestrogensonitsexpressionandlocalizationtodeterminewhetheradisturbanceinthissignalingpathwayisinvolvedinmediatingtheestrogenizedphenotype.emShh/emwasexpressedinepithelialcellsatthedistaltipsofelongatingductsindiscreet,heterogeneousfoci,whileemptc/emandemgli/em1ndash;3wereexpressedintheadjacentmesenchymalcellsinthedevelopinggland.TheadditionofemShh/emproteintoculturedneonatalprostatesreducedductalgrowthandbranching,decreasedemFgf/em10transcript,andincreasedemBmp/em4expressionintheadjacentmesenchyme.emShh/em-inducedgrowthsuppressionwasreversedbyexogenousemFgf/em10,butnotemnoggin/em,indicatingthatemFgf/em10suppressionistheproximatecauseofthegrowthinhibition.AmodelisproposedtoshowhowhighlylocalizedemShh/emexpressionalongwithregulationofdownstreammorphogensparticipatesindichotomousbranchingduringprostatemorphogenesis.Neonatalexposuretohigh-doseestradiolsuppressedemShh/em,emptc/em,emgli/em1,andemgli/em3expressionsandconcomitantlyblockedductalbranchinginthedorsalandlateralprostatelobesspecifically.Incontrast,ventrallobebranchingandemShh-ptc-gli/emexpressionwereminimallyaffectedbyestrogenexposure.OrganculturestudieswithlateralprostatesconfirmedthatestradiolsuppressedemShh-ptc-gli/emexpressiondirectlyattheprostaticlevel.Takentogether,thepresentfindingsindicatethatlobe-specificdecreasesinemShh-ptc-gli/emexpressionareinvolvedinmediatingestradiol-inducedsuppressionofdorsalandlaterallobeductalgrowthandbranchingduringprostatemorphogenesis./p/div