Abstract
Endocardial to mesenchymal transformation (EMT) is a fundamental cellular process required for heart valve formation. Notch, Wnt and Bmp pathways are known to regulate this process. To further address how these pathways coordinate in the process, we specifically disrupted Notch1 or Jagged1 in the endocardium of mouse embryonic hearts and showed that Jagged1-Notch1 signaling in the endocardium is essential for EMT and early valvular cushion formation. qPCR and RNA in situ hybridization assays reveal that endocardial Jagged1-Notch1 signaling regulates Wnt4 expression in the atrioventricular canal (AVC) endocardium and Bmp2 in the AVC myocardium. Whole embryo cultures treated with Wnt4 or Wnt inhibitory factor 1 (Wif1) show that Bmp2 expression in the AVC myocardium is dependent on Wnt activity; Wnt4 also reinstates Bmp2 expression in the AVC myocardium of endocardial Notch1 null embryos. Furthermore, while both Wnt4 and Bmp2 rescue the defective EMT resulting from Notch inhibition, Wnt4 requires Bmp for its action. These results demonstrate that Jagged1-Notch1 signaling in endocardial cells induces the expression of Wnt4, which subsequently acts as a paracrine factor to upregulate Bmp2 expression in the adjacent AVC myocardium to signal EMT.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Bone Morphogenetic Protein 2 / genetics
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Bone Morphogenetic Protein 2 / metabolism*
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Embryo, Mammalian
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Endocardium / embryology
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Endocardium / metabolism*
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Epithelial-Mesenchymal Transition / genetics
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Extracellular Matrix Proteins / genetics
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Extracellular Matrix Proteins / metabolism
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Gene Expression Regulation, Developmental*
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Heart Valves / embryology
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Heart Valves / metabolism*
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Jagged-1 Protein
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Transgenic
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Myocardium / metabolism*
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Organogenesis / genetics
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Serrate-Jagged Proteins
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Signal Transduction
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Wnt4 Protein / genetics
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Wnt4 Protein / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Bmp2 protein, mouse
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Bone Morphogenetic Protein 2
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Calcium-Binding Proteins
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Extracellular Matrix Proteins
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Intercellular Signaling Peptides and Proteins
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Jag1 protein, mouse
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Jagged-1 Protein
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Membrane Proteins
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Notch1 protein, mouse
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Receptor, Notch1
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Serrate-Jagged Proteins
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Wif1 protein, mouse
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Wnt4 Protein
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Wnt4 protein, mouse