Differential activation of canonical Wnt signaling determines cranial sutures fate: A novel mechanism for sagittal suture craniosynostosis

摘要

Prematureclosureofcranialsutures,whichserveasgrowthcentersfortheskullvault,resultincraniosynostosis.Inthemouseposteriorfrontal(PF)sutureclosesbyendochondralossification,whereassagittal(SAG)remainpatentlifetime,althoughbothareneuralcresttissuederived.Wetherefore,investigatedwhycranialsuturesofsametissueoriginadoptadifferentfate.WedemonstratedthatclosureofthePFsutureistightlyregulatedbycanonicalWntsignaling,whereaspatencyoftheSAGsutureisachievedbyconstantlyactivatedcanonicalWntsignaling.Importantly,thefateofPFandSAGsuturescanbereversedbymanipulatingWntsignaling.ContinuousactivationofcanonicalWntsignalinginthePFsutureinhibitsendochondralossificationandtherefore,sutureclosure,Incontrast,inhibitionofcanonicalWntsignalingintheSAGsuture,upontreatmentwithWntantagonistsresultsinendochondralossificationandsutureclosure.Thus,inhibitionofcanonicalWntsignalingintheSAGsuturephenocopiescraniosynostosis.Moreover,micehaploinsufficientforemTwist1/em,atargetgeneofcanonicalWntsignalingwhichinhibitschondrogenesis,havesagittalcraniosynostosis.WeproposethatregulationofcanonicalWntsignalingisofcrucialimportanceduringthephysiologicalpatterningofPFandSAGsutures.Importantly,dysregulationofthispathwaymayleadtocraniosynostosis./p/div