Segregated Foxc2, NFATc1 and Connexin expression at normal developing venous valves, and Connexin-specific differences in the valve phenotypes of Cx37, Cx43, and Cx47 knockout mice

摘要

Venousvalves(VVs)arecriticalforunidirectionalbloodflowfromsuperficialanddeepveinstowardstheheart.Congenitalvalveaplasiaoragenesismay,insomecases,beadirectcauseofvasculardisease,motivatinganunderstandingofthemolecularmechanismsunderlyingthedevelopmentandmaintenanceofVVs.Threegapjunctionproteins(Connexins),Cx37,Cx43,andCx47,arespecificallyexpressedatVVsinahighlypolarizedfashion.VVsareabsentfromadultmicelackingCx37;howeveritisnotknownifCx37isrequiredfortheinitialformationofvalves.Inaddition,therequirementofCx43andCx47forVVdevelopmenthasnotbeenstudied.Here,weprovideadetaileddescriptionofCx37,Cx43,andCx47expressionduringmouseveindevelopmentandshowbygeneknockoutthateachCxisnecessaryfornormalvalvedevelopment.ThevalvephenotypesintheknockoutlinesexhibitCx-specificdifferences,however,includingwhetherperipheralorcentralVVsareaffectedbygeneinactivation.Inaddition,weshowthataemCx47/emnullmutationimpairsperipheralVVdevelopmentbutdoesnotaffectlymphaticvalveformation,afindingofsignificanceforunderstandinghowsomeemCX47/emmutationscauseinheritedlymphedemainhumans.Finally,wedemonstrateastrikingsegregationofFoxc2andNFATc1transcriptionfactorexpressionbetweenthedownstreamandupstreamfaces,respectively,ofdevelopingVVleafletsandshowthatthissegregationiscloselyassociatedwiththehighlypolarizedexpressionofCx37,Cx43,andCx47.ThepartitionofFoxc2andNFATc1expressionatVVleafletsmakesitunlikelythatthesefactorsdirectlycooperateduringtheleafletelongationstageofVVdevelopment./p/div