{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:11:52Z","timestamp":1787026312209,"version":"build-2736575974"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T00:00:00Z","timestamp":1615852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>\n                    Congenital heart disease (CHD) is the most common life-threatening congenital anomaly. CHD occurs due to defects in cardiovascular development, and the majority of CHDs are caused by a multifactorial inheritance mechanism, which refers to the interaction between genetic and environmental factors. During embryogenesis, the cardiovascular system is derived from at least four distinct cell lineages: the first heart field, second heart field, cardiac neural crest, and proepicardial organ. Understanding the genes involved in each lineage is essential to uncover the genomic architecture of CHD. Therefore, we provide an overview of recent research progress using animal models and mutation analyses to better understand the molecular mechanisms and pathways linking cardiovascular development and CHD. For example, we highlight our recent work on genes encoding three isoforms of inositol 1,4,5-trisphosphate receptors (IP\n                    <jats:sub>3<\/jats:sub>\n                    R1, 2, and 3) that regulate various vital and developmental processes, which have genetic redundancy during cardiovascular development. Specifically, IP\n                    <jats:sub>3<\/jats:sub>\n                    R1 and 2 have redundant roles in the atrioventricular cushion derived from the first heart field lineage, whereas IP\n                    <jats:sub>3<\/jats:sub>\n                    R1 and 3 exhibit redundancy in the right ventricle and the outflow tract derived from the second heart field lineage, respectively. Moreover, 22q11.2 deletion syndrome (22q11DS) is highly associated with CHD involving the outflow tract, characterized by defects of the cardiac neural crest lineage. However, our studies have shown that\n                    <jats:italic>TBX1<\/jats:italic>\n                    , a major genetic determinant of 22q11DS, was not expressed in the cardiac neural crest but rather in the second heart field, suggesting the importance of the cellular interaction between the cardiac neural crest and the second heart field. Comprehensive genetic analysis using the Japanese genome bank of CHD and mouse models revealed that a molecular regulatory network involving GATA6, FOXC1\/2, TBX1, SEMA3C, and FGF8 was essential for reciprocal signaling between the cardiac neural crest and the second heart field during cardiovascular development. Elucidation of the genomic architecture of CHD using induced pluripotent stem cells and next-generation sequencing technology, in addition to genetically modified animal models and human mutation analyses, would facilitate the development of regenerative medicine and\/or preventive medicine for CHD in the near future.\n                  <\/jats:p>","DOI":"10.3389\/fcvm.2021.653244","type":"journal-article","created":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T00:22:03Z","timestamp":1615854123000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Genetic and Cellular Interaction During Cardiovascular Development Implicated in Congenital Heart Diseases"],"prefix":"10.3389","volume":"8","author":[{"given":"Kazuki","family":"Kodo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Uchida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Yamagishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,16]]},"reference":[{"key":"B1","first-page":"53","article-title":"Congenital heart disease","volume-title":"Genetics in Cardiovascular Diseases: Genetics, Epidemiology and Prevention","author":"Nora","year":"1991"},{"key":"B2","first-page":"29","article-title":"Life-long managements for congenital heart diseases: from embryology to adult congenital heart diseases influencing the next generation","volume":"26","author":"Yamagishi","year":"2010","journal-title":"Pediatr Cardiol Cardiovasc Surg."},{"key":"B3","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1253\/circj.CJ-16-1343","article-title":"The complex genetic basis of congenital heart defects","volume":"81","author":"Akhirome","year":"2017","journal-title":"Circ J."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e653","DOI":"10.1161\/CIR.0000000000000606","article-title":"Genetic basis for congenital heart disease: Revisited: A scientific statement from the American Heart Association","volume":"138","author":"Pierpont","year":"2018","journal-title":"Circulation."},{"key":"B5","doi-asserted-by":"publisher","first-page":"879","DOI":"10.3390\/biom9120879","article-title":"Genetics of congenital heart disease","volume":"9","author":"Williams","year":"2019","journal-title":"Biomolecules."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1016\/j.cell.2006.09.003","article-title":"Making or breaking the heart: From lineage determination to morphogenesis","volume":"126","author":"Srivastava","year":"2006","journal-title":"Cell."},{"key":"B7","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1038\/nrg1710","article-title":"Building the mammalian heart from two sources of myocardial cells","volume":"6","author":"Buckingham","year":"2005","journal-title":"Nat Rev Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2296","DOI":"10.1253\/circj.cj-11-0636","article-title":"A decade of advances in the molecular embryology and genetics underlying congenital heart defects","volume":"75","author":"Kodo","year":"2011","journal-title":"Circ J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"18","DOI":"10.24509\/JPCCS.170105","article-title":"Current insights into genetics of congenital heart diseases: GATA and T-box cardiac transcription factors as the hotspot pathogenesis","volume":"1","author":"Kodo","year":"2017","journal-title":"J Pediatr Cardiol Card Surg."},{"key":"B10","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/s1534-5807(01)00040-5","article-title":"The arterial pole of the mouse heart forms from FGF10-expressing cells in pharyngeal mesoderm","volume":"1","author":"Kelly","year":"2001","journal-title":"Dev Cell."},{"key":"B11","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1006\/dbio.2001.0409","article-title":"The outflow tract of the heart is recruited from a novel heart-forming field","volume":"238","author":"Mjaatvedt","year":"2001","journal-title":"Dev Biol."},{"key":"B12","doi-asserted-by":"crossref","first-page":"3179","DOI":"10.1242\/dev.128.16.3179","article-title":"Conotruncal myocardium arises from a secondary heart field","volume":"128","author":"Waldo","year":"2001","journal-title":"Development."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1126\/science.6844926","article-title":"Neural crest cells contribute to normal aorticopulmonary septation","volume":"220","author":"Kirby","year":"1983","journal-title":"Science."},{"key":"B14","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.semcdb.2006.12.004","article-title":"Model systems for the study of heart development and disease. 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