Negative regulation of Shh levels by Kras and Fgfr2 during hair follicle development

摘要

ActivatingmutationsintheemKRAS/emoncogeneareassociatedwiththreerelatedhumansyndromes,whichvaryinhairandskinphenotypesdependingontheinvolvedallele.HowvariationsinRASsignalsareinterpretedduringhairandskindevelopmentisunknown.Inthisstudy,weinvestigatedthedevelopmentalandtranscriptionalresponseofskinandhairtochangesinRASactivity,usingmousegeneticmodelsandmicroarrayanalysis.WhileactivationofemKras/em(emKras/emsupemG12D/em/sup)intheskinhadstrongeffectsonhairgrowthandhairshape,steadystatechangesindownstreamRAS/MAPKeffectorsweresubtleanddetectedonlybytranscriptionalresponses.TomodelthetranscriptionalresponseofmultipledevelopmentalpathwaystoactiveRAS,theeffectsofgrowthfactorstimulationwerestudiedinskinexplants.HereFGFacutelysuppressedemShh/emtranscriptionwithin90#xA0;minbuthadsignificantlylesseffectonEda,WNT,NotchorBMPpathways.Furthermore,eminvivoFgfr2/emloss-of-functionintheectodermcausedderepressionofemShh/em,revealingaroleforFGFinemShh/emregulationinthehairfollicle.ThesestudiesdefinebothdosagesensitiveeffectsofRASsignalingonhairmorphogenesisandrevealacutemechanismsforfine-tuningemShh/emlevelsinthehairfollicle./p/div