Fibroblast Growth Factor Receptor 2-IIIb Acts Upstream of Shh and Fgf4 and Is Required for Limb Bud Maintenance but Not for the Induction of Fgf8, Fgf10, Msx1, or Bmp4

摘要

MicedeficientforemFgfR2-IIIb/emweregeneratedbyplacingtranslationalstopcodonsandanIRES-emLac/emZcassetteintoexonIIIbofemFgfR2/em.Expressionofthealternativelysplicedreceptorisoform,emFgfR2-IIIc/em,wasnotaffectedinmicedeficientfortheIIIbisoform.emFgfR2-IIIb/emsupminus;/minus;/supsuplac/supsupZ/supmicesurvivetotermbutshowdysgenesisofthekidneys,salivaryglands,adrenalglands,thymus,pancreas,skin,oticvesicles,glandularstomach,andhairfollicles,andagenesisofthelungs,anteriorpituitary,thyroid,teeth,andlimbs.DetailedanalysisoflimbdevelopmentrevealedanessentialroleforFgfR2-IIIbinmaintainingtheAER.ItsabsencedidnotpreventexpressionofemFgf8/em,emFgf10/em,emBmp4,/emandemMsx1/em,butdidpreventinductionofemShh/emandemFgf4/em,indicatingthattheyaredownstreamtargetsofemFgfR2-IIIb/emactivation.IntheabsenceofFgfR2-IIIb,extensiveapoptosisofthelimbbudectodermandmesenchymeoccursbetweenE10andE10.5,providingevidencethatFgfsactprimarilyassurvivalfactors.WeproposethatFgfR2-IIIbisnotrequiredforlimbbudinitiation,butisessentialforitsmaintenanceandgrowth./p/div