BMP antagonism by Noggin is required in presumptive notochord cells for mammalian foregut morphogenesis

摘要

Esophagealatresiawithtracheoesophagealfistula(EA/TEF)isaserioushumanbirthdefect,inwhichtheesophagusendsbeforereachingthestomach,andisaberrantlyconnectedwiththetrachea.SeveralmousemodelsofEA/TEFhaverecentlydemonstratedthatproperdorsal/ventral(D/V)patterningoftheprimitiveanteriorforegutendodermisessentialforcorrectcompartmentalizationofthetracheaandesophagus.HereweelucidatethepathogenicmechanismsunderlyingtheEA/TEFthatoccursinmicelackingtheBMPantagonistNoggin,whichdisplaycorrectdorsal/ventralpatterning.Toclarifythemechanismofthismalformation,weusespatiotemporalmanipulationofNogginandBMPreceptor1Aconditionalallelesduringforegutdevelopment.Surprisingly,wefindthattheexpressionofNoggininthecompartmentalizingendodermisnotrequiredtogeneratedistincttrachealandesophagealtubes.Instead,weshowthatNogginandBMPsignalingattenuationarerequiredintheearlynotochordtocorrectlyresolvenotochordcellsfromthedorsalforegutendoderm,whichinturn,appearstobeaprerequisiteforforegutcompartmentalization.Collectively,ourfindingssupportanemergingmodelforamechanismunderlyingEA/TEFinwhichimpairednotochordresolutionfromtheearlyendodermcausestheforeguttobehypo-cellularjustpriortothecriticalperiodofcompartmentalization.OurfurthercharacterizationssuggestthatNogginmayregulateacellrearrangementprocessthatinvolvesreciprocalE-cadherinandemZeb1/emexpressionintheresolvingnotochordcells./p/div