The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development

摘要

Accumulatingevidencesuggeststhatinthevertebrateembryo,acquisitionofarterialandvenousidentityisestablishedearlybygeneticmechanisms,includingthoseregulatedbyvascularendothelialgrowthfactor(VEGF)andNotchsignaling.However,althoughtheCOUP-TFIInuclearreceptorhasrecentlybeenshowntoregulateveinidentity,verylittleisknownaboutthemolecularmechanismsoftranscriptionalregulationinarterialspecification.Here,weshowthatmouseembryoscompoundmutantforemFoxc1/emandemFoxc2/em,twocloselyrelatedFoxtranscriptionfactors,exhibitarteriovenousmalformationsandlackofinductionofarterialmarkerswhereasvenousmarkerssuchasCOUP-TFIIarenormallyexpressed,suggestingthatmutantendothelialcellsfailtoacquireanarterialfate.Notably,consistentwiththisobservation,overexpressionofemFoxc/emgenesinvitroinducesexpressionofarterialmarkerssuchasemNotch1/emanditsligandemDelta-like4/em(emDll4/em),andFoxc1andFoxc2directlyactivatetheemDll4/empromoterviaaFoxc-bindingsite.Moreover,compoundemFoxc/emmutantsshowadefectinsproutingoflymphaticendothelialcellsfromveinsinearlylymphaticdevelopment,duetoreducedexpressionofemVEGF-C/em.Takentogether,ourresultsdemonstratethatFoxctranscriptionfactorsarenovelregulatorsofarterialcellspecificationupstreamofNotchsignalingandlymphaticsproutingduringembryonicdevelopment./p/div