Mutations in Hedgehog Acyltransferase (Hhat) Perturb Hedgehog Signaling, Resulting in Severe Acrania-Holoprosencephaly-Agnathia Craniofacial Defects 英文参考文献.docVIP

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Mutations in Hedgehog Acyltransferase (Hhat) Perturb Hedgehog Signaling, Resulting in Severe Acrania-Holoprosencephaly-Agnathia Craniofacial Defects 英文参考文献.doc

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Mutations in Hedgehog Acyltransferase (Hhat) Perturb Hedgehog Signaling, Resulting in Severe Acrania-Holoprosencephaly-Agnathia Craniofacial Defects 英文参考文献

MutationsinHedgehogAcyltransferase(Hhat)Perturb HedgehogSignaling,ResultinginSevereAcrania- Holoprosencephaly-AgnathiaCraniofacialDefects JenniferF.Dennis1,2,HiroshiKurosaka1,AngeloIulianella1,3,JenniferPace1,NancyThomas1, SharonBeckham1,TrevorWilliams4,PaulA.Trainor1,2* 1StowersInstituteforMedicalResearch,KansasCity,Missouri,UnitedStatesofAmerica,2DepartmentofAnatomyandCellBiology,UniversityofKansasMedicalCenter, Kansas City, Kansas, United States of America, 3Department of Anatomy and Neurobiology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada, 4DepartmentofCellBiology,StemCells,andDevelopment,UniversityofColoradoDenver,Aurora,Colorado,UnitedStatesofAmerica Abstract Holoprosencephaly(HPE)isafailureoftheforebraintobifurcateandisthemostcommonstructuralmalformationofthe embryonicbrain.MutationsinSHHunderliemostfamilial(17%)casesofHPE;and,consistentwiththis,Shhisexpressedin midlineembryoniccellsandtissuesandtheirderivativesthatareaffectedinHPE.Ithaslongbeenrecognizedthatagraded seriesoffacialanomaliesoccurswithintheclinicalspectrumofHPE,asHPEisoftenfoundinpatientstogetherwithother malformationssuchasacrania,anencephaly,andagnathia.However,itisnotknownifthesephenotypesarisethrougha common etiology and pathogenesis. Here we demonstrate for the first time using mouse models that Hedgehog acyltransferase (Hhat) loss-of-function leads to holoprosencephaly together with acrania and agnathia, which mimics the severeconditionobservedinhumans.Hhatisrequiredforpost-translationalpalmitoylationofHedgehog(Hh)proteins;and, in the absence of Hhat, Hh secretion from producing cells is diminished. We show through downregulation of the Hh receptor Ptch1 that loss of Hhat perturbs long-range Hh signaling, which in turn disrupts Fgf, Bmp and Erk signaling. Collectively, this leads to abnormal patterning and extensive apoptosis within the craniofacial primordial, together with defectsincartilageandbonedifferentiation.ThereforeourworkshowsthatHhatloss-of-functi