DiGeorge Syndrome, Tbx1, and Retinoic Acid Signaling Come Full Circle

Abstract

See related article, pages 686-694 Among the most well-characterized cardiac congenital malformations are those associated with DiGeorge syndrome (DGS)/velocardiofacial syndrome. DGS is mainly caused by heterozygous deletion of a region of chromosome 22q11.2 and is characterized by cardiac conotruncal malformations, aortic arch anomalies, dysmorphic face and hypoplasia of the thymus and parathyroid.1 This spectrum of anomalies is attributed to defects in neural crest-derived structures and associated tissues. The T-box-containing transcription factor TBX1 has been identified as responsible for cardiovascular, thymic, and parathyroid phenotypes of DGS.2 Alterations in retinoic acid (RA) metabolism are similarly associated with cardiac conotruncal, aortic arch, and pharyngeal structural abnormalities similar to DGS.3 In this issue of Circulation Research , Ryckebusch et al4 establish a new functional link between Tbx1 and RA signaling in the regulation of aortic arch anomalies in a mouse model of DGS. A characteristic feature of DGS is malformation of the pharyngeal arch arteries (PAAs), particularly of the fourth PAA, which leads to interrupted aortic arch type B (IAA-B). Mice heterozygous for Tbx1 exhibit defects in the development in the fourth PAA related to aortic arch anomalies including IAA.5,6 Ryckebusch et al define molecular and cellular mechanisms underlying aortic arch anomalies in Tbx1 +/− mice.4 The fourth PAA in embryonic day 10.5 embryos is derived from neural crest cells and is absent or hypomorphic in Tbx1 +/− embryos. This PAA anomaly is accompanied by neural crest migration defects as well as inhibition of vascular smooth muscle (VSM) differentiation. Both neural crest migration and VSM differentiation related to PAA defects are controlled by a precise balance of RA signaling …