Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes

摘要

Growth/differentiationfactors5,6,and7(GDF5/6/7)representadistinctsubgroupwithinthebonemorphogeneticprotein(BMP)familyofsecretedsignalingmolecules.PreviousstudieshaveshownthattheemGdf5/emgeneisexpressedintransversestripesacrossdevelopingskeletalelementsandisoneoftheearliestknownmarkersofjointformationduringembryonicdevelopment.Althoughnullmutationsinthisgenedisruptformationofsomebonesandjointsintheskeleton,manysitesareunaffected.Here,weshowthatthecloselyrelatedfamilymembersemGdf6/emandemGdf7/emareexpressedindifferentsubsetsofdevelopingjoints.InactivationoftheemGdf6/emgenecausesdefectsinjoint,ligament,andcartilageformationatsitesdistinctfromthoseseeninemGdf5/emmutants,includingthewristandankle,themiddleear,andthecoronalsuturebetweenbonesintheskull.MicelackingbothemGdf5/emandemGdf6/emshowadditionaldefects,includingseverereductionorlossofsomeskeletalelementsinthelimb,additionalfusionsbetweenskeletalstructures,scoliosis,andalteredcartilageintheintervertebraljointsofthespinalcolumn.TheseresultsshowthatmembersoftheGDF5/6/7subgrouparerequiredfornormalformationofbonesandjointsinthelimbs,skull,andaxialskeleton.ThediverseeffectsonjointdevelopmentandthedifferenttypesofjointsaffectedinthemutantssuggestthatmembersoftheGDFfamilyplayakeyroleinestablishingboundariesbetweenmanydifferentskeletalelementsduringnormaldevelopment.Someoftheskeletaldefectsseeninsingleordoublemutantmiceresembledefectsseeninhumanskeletaldiseases,whichsuggeststhatthesegenesmaybecandidatesthatunderliesomeformsofcarpal/tarsalcoalition,conductivedeafness,scoliosis,andcraniosynostosis./p/div