Heartformationiscuedbyacombinationofpositiveandnegativesignalsfromsurroundingtissues.InhibitorysignalsthatblockheartformationinanteriorparaxialmesodermincludeWntfamilymembersexpressedindorsalneuraltubeandanti-BMPsexpressedintheaxialtissues(i.e.,noggininthenotochord).Wntsignallingpathway,whichisessentialforsettinguptheentirebodypatternduringembryonicdevelopmentinvolvesglycogensynthasekinase-3(GSK3).IntheabsenceofWntsignaling,GSK3isactiveandphosphorylatesb-cateninresultinginitsdegradationbyubiquitin-mediatedproteolysis.ActivationofWntsignalinginhibitsGSK3,therebypreventingphosphorylationofb-catenin,whichisthenabletomovetothenucleus.ThereitassociateswithmembersoftheLEF-1/TCFfamilyoftranscriptionfactors,whichactivatethetranscriptionofgeneslikecyclin-D1,myc,andMMPs.TheWntsignalingpathwayisblockedbyafamilyofsecretedproteinssuchascrescentandDkk-1sufficientforinductionofheartformationinposteriormesoderm.BMPsignalingcanalsobeblockedbytheBMPantagoNISTsnogginandchordin,whicharesecretedfromthenotochordandcooperatewithWntstopreventcardiogenesis.ReceptorsforBMPs,membersofthetransforminggrowthfactor-beta(TGFb)superfamily,arepersistentlyexpressedduringcardiacdevelopment,yetmicelackingtypeIIortypeIABMPreceptorsdieatgastrulationandcannotbeusedtoassesspotentiallaterrolesincreationoftheheart.Activinreceptor-likekinase3(ALK3)isspecificallyrequiredatmid-gestationfornormaldevelopmentofthetrabeculae,compactmyocardium,interventricularseptum,andendocardialcushion.CardiacmusclelackingALK3isspecificallydeficientinexpressingTGFb2,anestablishedparacrinemediatorofcushionmorphogenesis.Inhumans,congenitalheartdefectsoccurwithaprevalenceofatleast1%innewborns,andareevenmorecommonindeathbeforeterm.Mostfrequentaredefectsinseptationandthecardiacvalves,andfewsinglegeneetiologiesareknown.TheinvariabledefectsinmyocardiumandAVcushionresultingfromcongenitaldeletionofALK3providestrongsupportforitsassessmentasacandidategeneinhumancongenitalheartdisease.

Contributor:KosiGramatikoff

REFERENCES:FrameS,CohenP.GSK3takescentrestagemorethan20yearsafteritsdiscovery.BiochemJ.(2001)Oct1;359(Pt1):1-16.Review.GaussinV,etal.,Endocardialcushionandmyocardialdefectsaftercardiacmyocyte-specificconditionaldeletionofthebonemorphogeneticproteinreceptorALK3.ProcNatlAcadSciUSA.(2002)Mar5;99(5):2878-83.MarvinMJetal.InhibitionofWntactivityinducesheartformationfromposteriormesoderm.GenesDev.(2001)Feb1;15(3):316-27.SchneiderVA.AndMercolaM.WntantagonisminitiatescardiogenesisinXenopuslaevis.GenesDev.(2001)Feb1;15(3):304-15.TzahorE.andLassarAB.Wntsignalsfromtheneuraltubeblockectopiccardiogenesis.GenesDev.(2001)Feb1;15(3):255-60.