{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T04:10:54Z","timestamp":1790395854681,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2013,4,23]],"date-time":"2013-04-23T00:00:00Z","timestamp":1366675200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Variations and mutations in the human genome, such as 22q11.2 microdeletion, can increase the risk for congenital defects, including aortic arch malformations. Animal models are increasingly expanding our molecular and genetic insights into aortic arch development. However, in order to justify animal\u2010to\u2010human extrapolations, a human morphological, and molecular reference model would be of great value, but is currently lacking. Here, we present interactive three\u2010dimensional reconstructions of the developing human aortic arch system, supplemented with the protein distribution of developmental markers for patterning and growth, including T\u2010box transcription factor TBX1, a major candidate for the phenotypes found in patients with the 22q11.2 microdeletion. These reconstructions and expression data facilitate unbiased interpretations, and reveal previously unappreciated aspects of human aortic arch development. Based on our reconstructions and on reported congenital anomalies of the pulmonary trunk and tributaries, we postulate that the pulmonary arteries originate from the aortic sac, rather than from the sixth pharyngeal arch arteries. Similar to mouse, TBX1 is expressed in pharyngeal mesenchyme and epithelia. The endothelium of the pharyngeal arch arteries is largely negative for TBX1 and family member TBX2 but expresses neural crest marker AP2\u03b1, which gradually decreases with ongoing development of vascular smooth muscle. At early stages, the pharyngeal arch arteries, aortic sac, and the dorsal aortae in particular were largely negative for proliferation marker Ki67, potentially an important parameter during aortic arch system remodeling. Together, our data support current animal\u2010to\u2010human extrapolations and future genetic and molecular analyses using animal models of congenital heart disease. \u00a9 2013 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.35881","type":"journal-article","created":{"date-parts":[[2013,4,23]],"date-time":"2013-04-23T21:12:53Z","timestamp":1366751573000},"page":"1372-1383","source":"Crossref","is-referenced-by-count":41,"title":["Development of the human aortic arch system captured in an interactive three\u2010dimensional reference model"],"prefix":"10.1002","volume":"164","author":[{"given":"M. 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