{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:29:11Z","timestamp":1760401751856,"version":"build-2065373602"},"reference-count":52,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2014,12,9]],"date-time":"2014-12-09T00:00:00Z","timestamp":1418083200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL60714"],"award-info":[{"award-number":["HL60714"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["12PRE9430047"],"award-info":[{"award-number":["12PRE9430047"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Developmental Dynamics"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:p><jats:styled-content>Background:<\/jats:styled-content> Multiple bone morphogenetic protein (BMP) genes are expressed in the developing heart from the initiation to late\u2010differentiation stages, and play pivotal roles in cardiovascular development. In this study, we investigated the requirement of BMP activity in heart development by transgenic over\u2010expression of extracellular BMP antagonist Noggin. <jats:bold><jats:styled-content>Results:<\/jats:styled-content><\/jats:bold> Using <jats:italic>Nkx2.5\u2010Cre<\/jats:italic> to drive lineage\u2010restricted <jats:italic>Noggin<\/jats:italic> within cardiomyocyte progenitors, we show persistent Noggin arrests cardiac development at the linear heart stage. This is coupled with a significantly reduced cell proliferation rate, subsequent cardiomyocyte programmed cell death and reduction of downstream intracellular pSMAD1\/5\/8 expression. <jats:italic>Noggin<\/jats:italic> mutants exhibit reduced heartbeat which likely results in subsequent fully penetrant in utero lethality. Significantly, confocal and electron micrographic examination revealed considerably fewer contractile elements, as well as a lack of maturation of actin\u2010myosin microfilaments. Molecular analysis demonstrated that ectopic Noggin\u2010expressing regions in the early heart's pacemaker region, failed to express the potassium\/sodium hyperpolarization\u2010activated cyclic nucleotide\u2010gated channel 4 (<jats:italic>Hcn4<\/jats:italic>), resulting in an overall decrease in <jats:italic>Hcn4<\/jats:italic> levels. <jats:bold><jats:styled-content>Conclusions:<\/jats:styled-content><\/jats:bold> Combined, our results reveal a novel role for BMP signaling in the progression of heart development from the tubular heart stage to the looped stage by means of regulation of proliferation and promotion of maturation of the in utero heart's contractile apparatus and pacemaker. <jats:italic>Developmental Dynamics 244:457\u2013467, 2015<\/jats:italic>. \u00a9 2014 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/dvdy.24233","type":"journal-article","created":{"date-parts":[[2014,11,26]],"date-time":"2014-11-26T13:54:05Z","timestamp":1417010045000},"page":"457-467","source":"Crossref","is-referenced-by-count":5,"title":["Persistent Noggin arrests cardiomyocyte morphogenesis and results in early in utero lethality"],"prefix":"10.1002","volume":"244","author":[{"given":"Olga","family":"Simmons","sequence":"first","affiliation":[{"name":"Developmental Biology and Neonatal Medicine Program HB Wells Center for Pediatric Research, Indiana University School of Medicine Indianapolis Indiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paige","family":"Snider","sequence":"additional","affiliation":[{"name":"Developmental Biology and Neonatal Medicine Program HB Wells Center for Pediatric Research, Indiana University School of Medicine Indianapolis 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