Foxh1 is essential for development of the anterior heart field.
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.
von Both
Ingo
I
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
Silvestri
Cristoforo
C
Erdemir
Tuba
T
Lickert
Heiko
H
Walls
Johnathon R
JR
Henkelman
R Mark
RM
Rossant
Janet
J
Harvey
Richard P
RP
Attisano
Liliana
L
Wrana
Jeffrey L
JL
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
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