All authors declare no conflict of interest related to this article.
Development of the human aortic arch system captured in an interactive three-dimensional reference model
Article first published online: 23 APR 2013
© 2013 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 164, Issue 6, pages 1372–1383, June 2014
How to Cite
2012. Development of the human aortic arch system captured in an interactive three-dimensional reference model. Am J Med Genet Part A. 321A:1372–1383., , , .
M. Sameer Rana and Aleksander Sizarov contributed equally to this work.
- Issue published online: 7 MAY 2014
- Article first published online: 23 APR 2013
- Manuscript Accepted: 31 DEC 2012
- Manuscript Received: 20 SEP 2012
- European Community's Framework Programmes. Grant Number: LSHM-CT-2005-018630
- Netherlands Organization for Scientific Research. Grant Number: 017.004.040
- Estonian Science Foundation. Grant Number: 7301
- human embryos;
- aortic arch system;
- aortic arch malformations;
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-to-human extrapolations, a human morphological, and molecular reference model would be of great value, but is currently lacking. Here, we present interactive three-dimensional reconstructions of the developing human aortic arch system, supplemented with the protein distribution of developmental markers for patterning and growth, including T-box 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 AP2α, 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-to-human extrapolations and future genetic and molecular analyses using animal models of congenital heart disease. © 2013 Wiley Periodicals, Inc.