Wnt7b is required for epithelial progenitor growth and operates during epithelial-to-mesenchymal signaling in pancreatic development

摘要

Wntsignalingisawellconservedpathwaycriticalforgrowth,patterninganddifferentiationofmultipletissuesandorgans.PreviousstudiesonWntsignalinginthepancreashavebeenbasedpredominantlyondownstreampathwayeffectorgenessuchasβ-catenin.Wehereprovideevidencethatthecanonical-pathwaymemberWnt7bisaphysiologicalregulatorofpancreaticprogenitorcellgrowth.GeneticdeletionofemWnt7b/eminthedevelopingpancreasleadstopancreatichypoplasiaduetoreducedproliferationofpancreaticprogenitorcellsduringthephaseofpancreasdevelopmentmarkedbyrapidprogenitorcellgrowth.WhilethedifferentiationpotentialofpancreaticprogenitorcellsisunaffectedbyemWnt7b/emdeletion,throughagain-of-functionanalysis,wefindthatearlypancreaticprogenitorcellsarehighlysensitivetoWnt7bexpression,butlaterlosesuchcompetence.BymodulatingthelevelandthetemporalwindowsofWnt7bexpressionwedemonstrateasignificantimpactonorgangrowthandmorphogenesisparticularlyduringtheearlybranchingstagesoftheorgan,whichnegativelyaffectsgenerationofthepro-endocrine(Ngn3sup+/sup/Nkx6.1sup+/sup),andpro-acinar(Ptf1Asup+/sup)fields.Consequently,Wnt7bgain-of-functionresultsinfailedmorphogenesisandalmostcompleteabrogationofthedifferentiationofendocrineandacinarcells,leadingtocysticepithelialmetaplasiaexpressingductalmarkersincludingSox9,Hnf6andHnf1β.WhileWnt7bisexpressedexclusivelyinthedevelopingpancreaticepithelium,adjacentmesenchymalcellsintheorgandisplayadirecttrophicresponsetoelevatedWnt7bandincreaseexpressionofLef1,cFosanddesmin.Ofnote,incontrasttothepancreaticepithelium,thepancreaticmesenchymeremainscompetenttorespondtoWnt7bligand,atlaterstagesindevelopment.WeconcludethatWnt7bhelpscoordinatepancreaticdevelopmentthroughautocrine,aswellasparacrinemechanisms,andassuchrepresentsanovelbi-modalmorphogenligand./p/div