title: Foxh1 is essential for development of the anterior heart field.
abstract: The anterior heart field (AHF) mediates formation of the outflow tract (OFT) and right ventricle (RV) during looping morphogenesis of the heart. Foxh1 is a forkhead DNA binding transcription factor in the TGFbeta-Smad pathway. Here we demonstrate that Foxh1-/- mutant mouse embryos form a primitive heart tube, but fail to form OFT and RV and display loss of outer curvature markers of the future working myocardium, similar to the phenotype of Mef2c-/- mutant hearts. Further, we show that Mef2c is a direct target of Foxh1, which physically and functionally interacts with Nkx2-5 to mediate strong Smad-dependent activation of a TGFbeta response element in the Mef2c gene. This element directs transgene expression to the presumptive AHF, as well as the RV and OFT, a pattern that closely parallels endogenous Mef2c expression in the heart. Thus, Foxh1 and Nkx2-5 functionally interact and are essential for development of the AHF and its derivatives, the RV and OFT, in response to TGFbeta-like signals.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Ingo
authors.initials: I
authors.lastname: von Both
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Silvestri
authors.forename: Tuba
authors.initials: T
authors.lastname: Erdemir
authors.forename: Heiko
authors.initials: H
authors.lastname: Lickert
authors.forename: Johnathon R
authors.initials: JR
authors.lastname: Walls
authors.forename: R Mark
authors.initials: RM
authors.lastname: Henkelman
authors.forename: Janet
authors.initials: J
authors.lastname: Rossant
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
authors.forename: Liliana
authors.initials: L
authors.lastname: Attisano
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
mesh_terms: D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002454:Cell Differentiation; D003001:Cloning, Molecular; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology; D004625:Embryo, Nonmammalian; D004742:Enhancer Elements, Genetic; D051858:Forkhead Transcription Factors; D005982:Glutathione Transferase / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D017403:In Situ Hybridization; D007438:Introns; D064326:MEF2 Transcription Factors; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018006:Myogenic Regulatory Factors / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D015027:Zebrafish; D029961:Zebrafish Proteins
chemical_list: D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C491117:Foxh1 protein, mouse; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029961:Zebrafish Proteins; C491116:foxh1 protein, zebrafish; D012313:RNA; D004247:DNA; D005982:Glutathione Transferase