Mouse GLI3 Regulates Fgf8 Expression and Apoptosis in the Developing Neural Tube, Face, and Limb Bud

[摘要] ThezincfingertranscriptionfactorGLI3isconsideredarepressorofvertebrateHedgehog(Hh)signaling.Inhumans,theabsenceofGLI3functioncausesGreigcephalopolysyndactylysyndrome,affectingthedevelopmentofthebrain,eye,face,andlimb.Becausetheetiologyofthesemalformationsisnotwellunderstood,weexaminedthephenotypeofmouseGli3−/−mutantsasamodeltoinvestigatethis.Weobservedanup-regulationofFgf8intheanteriorneuralridge,isthmus,eye,facialprimordia,andlimbbudsofmutantembryos,sitescoincidingwiththehumandisease.Intriguingly,endogenousapoptosiswasreducedinFgf8-positiveareasinGli3−/−mutants.SinceSHHisthoughttobeinvolvedinFgf8regulation,wecomparedFgf8expressioninShh−/−andGli3−/−;Shh−/−mutantembryos.WhereasFgf8expressionwasalmostabsentinShh−/−mutants,itwasup-regulatedinGli3−/−;Shh−/−doublemutants,suggestingthatSHHisnotrequiredforFgf8induction,andthatGLI3normallyrepressesFgf8independentlyofSHH.Inthelimbbud,weprovideevidencethatectopicexpressionofGremlininGli3−/−mutantsmightcontributetoadecreaseinapoptosis.Together,ourdatarevealthatGLI3limitsFgf8-expressiondomainsinmultipletissues,throughamechanismthatmayincludetheinductionormaintenanceofapoptosis.

[学科分类] 生物科学（综合）

[关键词] GLI3;FGF8;SHH;brain patterning;optic field;limb development;facial malformation;apoptosis