{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:27:57Z","timestamp":1790008077010,"version":"4.0.1"},"reference-count":64,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2016,5,13]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              The Notch signaling pathway is crucial for primitive cardiac valve formation by epithelial\u2013mesenchymal transition, and\n              <jats:italic>NOTCH1<\/jats:italic>\n              mutations cause bicuspid aortic valve; however, the temporal requirement for the various Notch ligands and receptors during valve ontogeny is poorly understood.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>The aim of this study is to determine the functional specificity of Notch in valve development.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              Using cardiac-specific conditional targeted mutant mice, we find that endothelial\/endocardial deletion of Mib1-Dll4-Notch1 signaling, possibly favored by Manic-Fringe, is specifically required for cardiac epithelial\u2013mesenchymal transition. Mice lacking endocardial\n              <jats:italic>Jag1<\/jats:italic>\n              ,\n              <jats:italic>Notch1<\/jats:italic>\n              , or\n              <jats:italic>RBPJ<\/jats:italic>\n              displayed enlarged valve cusps, bicuspid aortic valve, and septal defects, indicating that endocardial Jag1 to Notch1 signaling is required for post\u2013epithelial\u2013mesenchymal transition valvulogenesis. Valve dysmorphology was associated with increased mesenchyme proliferation, indicating that Jag1-Notch1 signaling restricts mesenchyme cell proliferation non\u2013cell autonomously. Gene profiling revealed upregulated Bmp signaling in\n              <jats:italic>Jag1<\/jats:italic>\n              -mutant valves, providing a molecular basis for the hyperproliferative phenotype. Significantly, the negative regulator of mesenchyme proliferation,\n              <jats:italic>Hbegf<\/jats:italic>\n              , was markedly reduced in\n              <jats:italic>Jag1<\/jats:italic>\n              -mutant valves.\n              <jats:italic>Hbegf<\/jats:italic>\n              expression in embryonic endocardial cells could be readily activated through a RBPJ-binding site, identifying\n              <jats:italic>Hbegf<\/jats:italic>\n              as an endocardial Notch target. Accordingly, addition of soluble heparin-binding EGF-like growth factor to\n              <jats:italic>Jag1<\/jats:italic>\n              -mutant outflow tract explant cultures rescued the hyperproliferative phenotype.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>During cardiac valve formation, Dll4-Notch1 signaling leads to epithelial\u2013mesenchymal transition and cushion formation. Jag1-Notch1 signaling subsequently restrains Bmp-mediated valve mesenchyme proliferation by sustaining Hbegf-EGF receptor signaling. Our studies identify a mechanism of signaling cross talk during valve morphogenesis involved in the origin of congenital heart defects associated with reduced NOTCH function.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.115.308077","type":"journal-article","created":{"date-parts":[[2016,5,12]],"date-time":"2016-05-12T20:19:18Z","timestamp":1463084358000},"page":"1480-1497","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":125,"title":["Sequential Ligand-Dependent Notch Signaling Activation Regulates Valve Primordium Formation and Morphogenesis"],"prefix":"10.1161","volume":"118","author":[{"given":"Donal","family":"MacGrogan","sequence":"first","affiliation":[{"name":"From the Intercellular Signaling in Cardiovascular Development and Disease Laboratory (D.M., G.D., S.T., B.M.-P., G.L., G.d.M.-N., T.P., M.S., V.B., J.L.d.l.P.), Regulation of Gene Expression in Vascular Endothelium Laboratory (P.G.-d. A., J.M.R.), Bioinformatics Unit (M.J.G.), and Cardiovascular Imaging Laboratory (L.J.J.-B.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Department of Molecular Biology, Universidad Aut\u00f3noma de Madrid, Madrid, Spain (P.G.-d. A.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"D\u2019Amato","sequence":"additional","affiliation":[{"name":"From the Intercellular Signaling in Cardiovascular Development and Disease Laboratory (D.M., G.D., S.T., B.M.-P., G.L., G.d.M.-N., T.P., M.S., V.B., J.L.d.l.P.), Regulation of Gene Expression in Vascular Endothelium Laboratory (P.G.-d. A., J.M.R.), Bioinformatics Unit (M.J.G.), and Cardiovascular Imaging Laboratory (L.J.J.-B.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Department of Molecular Biology, Universidad Aut\u00f3noma de Madrid, Madrid, Spain (P.G.-d. A.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislao","family":"Travisano","sequence":"additional","affiliation":[{"name":"From the Intercellular Signaling in Cardiovascular Development and Disease Laboratory (D.M., G.D., S.T., B.M.-P., G.L., G.d.M.-N., T.P., M.S., V.B., J.L.d.l.P.), Regulation of Gene Expression in Vascular Endothelium Laboratory (P.G.-d. A., J.M.R.), Bioinformatics Unit (M.J.G.), and Cardiovascular Imaging Laboratory (L.J.J.-B.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Department of Molecular Biology, Universidad Aut\u00f3noma de Madrid, Madrid, Spain (P.G.-d. A.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Martinez-Poveda","sequence":"additional","affiliation":[{"name":"From the Intercellular Signaling in Cardiovascular Development and Disease Laboratory (D.M., G.D., S.T., B.M.-P., G.L., G.d.M.-N., T.P., M.S., V.B., J.L.d.l.P.), Regulation of Gene Expression in Vascular Endothelium Laboratory (P.G.-d. A., J.M.R.), Bioinformatics Unit (M.J.G.), and Cardiovascular Imaging Laboratory (L.J.J.-B.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Department of Molecular Biology, Universidad Aut\u00f3noma de Madrid, Madrid, Spain (P.G.-d. A.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo","family":"Lux\u00e1n","sequence":"additional","affiliation":[{"name":"From the Intercellular Signaling in Cardiovascular Development and Disease Laboratory (D.M., G.D., S.T., B.M.-P., G.L., G.d.M.-N., T.P., M.S., V.B., J.L.d.l.P.), Regulation of Gene Expression in Vascular Endothelium Laboratory (P.G.-d. A., J.M.R.), Bioinformatics Unit (M.J.G.), and Cardiovascular Imaging Laboratory (L.J.J.-B.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Department of Molecular Biology, Universidad Aut\u00f3noma de Madrid, Madrid, Spain (P.G.-d. 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