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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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COS Cells
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Cell Differentiation
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Cloning, Molecular
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DNA / metabolism
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DNA, Complementary / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Embryo, Mammalian / cytology
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Embryo, Nonmammalian
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Enhancer Elements, Genetic
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Forkhead Transcription Factors
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Glutathione Transferase / metabolism
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Homeobox Protein Nkx-2.5
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Homeodomain Proteins / metabolism
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In Situ Hybridization
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Introns
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MEF2 Transcription Factors
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Mice
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Mice, Mutant Strains
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Mice, Transgenic
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Models, Biological
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Models, Genetic
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Molecular Sequence Data
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Mutation
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Myocardium / metabolism
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Myocardium / pathology
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Myogenic Regulatory Factors / biosynthesis
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Myogenic Regulatory Factors / genetics
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Phenotype
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RNA / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Stem Cells / cytology
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Time Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Transcription, Genetic
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Transfection
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Transforming Growth Factor beta / metabolism
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Transgenes / genetics
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Zebrafish
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Zebrafish Proteins*
Substances
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DNA, Complementary
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DNA-Binding Proteins
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Forkhead Transcription Factors
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Foxh1 protein, mouse
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Homeobox Protein Nkx-2.5
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Homeodomain Proteins
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MEF2 Transcription Factors
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Mef2c protein, mouse
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Myogenic Regulatory Factors
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Nkx2-5 protein, mouse
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Transcription Factors
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Transforming Growth Factor beta
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Zebrafish Proteins
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foxh1 protein, zebrafish
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RNA
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DNA
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Glutathione Transferase