Pbx1/Pbx2 govern axial skeletal development by controlling Polycomb and Hox in mesoderm and Pax1/Pax9 in sclerotome

摘要

Thepost-cranialaxialskeletonconsistsofametamericseriesofvertebralbodiesandintervertebraldiscs,aswellasadjoiningribsandsternum.PatterningofindividualvertebraeanddistinctregionsofthevertebralcolumnisaccomplishedbyPolycombandHoxproteinsintheparaxialmesoderm,whiletheirsubsequentmorphogenesisdependspartiallyonPax1/Pax9inthesclerotome.Inthisstudy,weuncoverthatemPbx1/Pbx2/emareco-expressedduringsuccessivestagesofvertebralandribdevelopment.Next,byexploitingaemPbx1/Pbx2/emloss-of-functionmouse,weshowthatdecreasingemPbx2/emdosageintheabsenceofemPbx1/emaffectsaxialdevelopmentmoreseverelythansinglelossofemPbx1/em.emPbx1/em/emPbx2/emmutantsexhibitahomogeneousvertebralcolumn,withlossofvertebralidentity,rudimentaryribs,androstralhindlimbshifts.Ofnote,theseaxialdefectsdonotarisefromperturbednotochordfunction,ascellularproliferation,apoptosis,andexpressionofregulatorsofnotochordsignalingarenormalinemPbx1/Pbx2/emmutants.WhiletheobserveddefectsareconsistentwithlossofPbxactivityasaHox-cofactorinthemesoderm,weadditionallyestablishthataxialskeletalpatterningandhindlimbpositioningaregovernedbyemPbx1/em/emPbx2/emthroughtheirgeneticcontrolofPolycombandemHox/emexpressionandspatialdistributioninthemesoderm,aswellasofemPax1/Pax9/eminthesclerotome./p/div