title: Endocardial to myocardial notch-wnt-bmp axis regulates early heart valve development.
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.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Wang
authors.forename: Bingruo
authors.initials: B
authors.lastname: Wu
authors.forename: Alyssa A
authors.initials: AA
authors.lastname: Chamberlain
authors.forename: Wendy
authors.initials: W
authors.lastname: Lui
authors.forename: Pratistha
authors.initials: P
authors.lastname: Koirala
authors.forename: Katalin
authors.initials: K
authors.lastname: Susztak
authors.forename: Diana
authors.initials: D
authors.lastname: Klein
authors.forename: Verdon
authors.initials: V
authors.lastname: Taylor
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D004699:Endocardium / Q000196:embryology / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006351:Heart Valves / Q000196:embryology / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D038081:Organogenesis / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D060528:Wnt4 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; C118544:Wif1 protein, mouse; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse
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