{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:01:28Z","timestamp":1790485288671,"version":"4.1.0"},"reference-count":49,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2020,1,1]],"date-time":"2020-01-01T00:00:00Z","timestamp":1577836800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1K08HL121191"],"award-info":[{"award-number":["1K08HL121191"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>The role played by Notch pathway in cardiac progenitor cell biology remains to be elucidated. Delta-like ligand-4 (Dll4), the arterial-specific Notch ligand, is expressed by second heart field (SHF) progenitors at time-points crucial in SHF biology. Dll4-mediated Notch signaling is critically required for maintaining an adequate pool of SHF progenitors, such that Dll4 knockout results in reduction in proliferation and increase in apoptosis. Reduced SHF progenitor pool leads to an underdeveloped right ventricle (RV) and outflow tract (OFT). In its most severe form, there is severe RV hypoplasia and poorly developed OFT resulting in early embryonic lethality. In milder form, the OFT is foreshortened and misaligned resulting in double outlet right ventricle. Dll4-mediated Notch signaling maintains Fgf8 expression by transcriptional regulation at the promoter level. Combined heterozygous knockout of Dll4 and Fgf8 demonstrates genetic synergy in OFT alignment. Exogenous supplemental Fgf8 rescues proliferation in Dll4 mutants in ex-vivo culture. Our results establish a novel role for Dll4-mediated Notch signaling in SHF biology. More broadly, our model provides a platform for understanding oligogenic inheritance that results in clinically relevant OFT malformations.<\/jats:p>","DOI":"10.1242\/dev.185249","type":"journal-article","created":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T16:40:32Z","timestamp":1597077632000},"source":"Crossref","is-referenced-by-count":16,"title":["Delta-like ligand-4 mediated Notch signaling controls proliferation of second heart field progenitor cells by regulating Fgf8 expression"],"prefix":"10.1242","author":[{"given":"Prashan","family":"De Zoysa","sequence":"first","affiliation":[{"name":"Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7702-4014","authenticated-orcid":false,"given":"Jiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Toubat","sequence":"additional","affiliation":[{"name":"Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jongkyu","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, USA"},{"name":"Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Molecular and Functional Genomics, Geisinger clinic, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parkash S.","family":"Gill","sequence":"additional","affiliation":[{"name":"Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Duarte","sequence":"additional","affiliation":[{"name":"Centro Interdisciplinar de Investiga\u00e7\u00e3o em Sanidade Animal, University of Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry M.","family":"Sucov","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical University of South Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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