Endothelin-3 regulates neural crest cell proliferation and differentiation in the hindgut enteric nervous system

摘要

Neuralcrestcells(NCC)migrate,proliferate,anddifferentiatewithinthewallofthegastrointestinaltracttogiverisetotheneuronsandglialcellsoftheentericnervoussystem(ENS).Theintestinalmicroenvironmentiscriticalinthisprocessandendothelin-3(ET3)isknowntohaveanessentialrole.Mutationsofthisgenecausedistalintestinalaganglionosisinrodents,butitsmechanismofactionispoorlyunderstood.WefindthatinhibitionofET3signalinginculturedavianintestinealsoleadstohindgutaganglionosis.TheaimofthisstudywastodeterminetheroleofET3duringformationoftheavianhindgutENS.Toanswerthisquestion,wecreatedchickndash;quailintestinalchimerasbytransplantingpreganglionicquailhindgutsintothecoelomiccavityofchickembryos.Thequailgraftsdeveloptwoganglionatedplexusesofdifferentiatedneuronsandglialcellsoriginatingentirelyfromthehostneuralcrest.ThepresenceofexcessET3inthegraftsresultsinasignificantincreaseinganglioncellnumber,whileinhibitionofendothelinreceptor-B(EDNRB)leadstoseverehypoganglionosis.TheET3-inducedhyperganglionosisisassociatedwithanincreaseinentericcrestcellproliferation.Usinghindgutexplantsculturedincollagengel,wefindthatET3alsoinhibitsneuronaldifferentiationintheENS.Finally,ET3,whichisstronglyexpressedinthececa,inhibitsthechemoattractionofNCCtoglial-derivedneurotrophicfactor(GDNF).OurresultsdemonstratemultiplerolesforET3signalingduringENSdevelopmentintheavianhindgut,whereitinfluencesNCCproliferation,differentiation,andmigration./p/div