Molecular Medicine Decreased Levels of Embryonic Retinoic Acid Synthesis Accelerate Recovery From Arterial Growth Delay in a Mouse Model of DiGeorge Syndrome

Rationale: Loss of Tbx1 and decrease of retinoic acid (RA) synthesis result in DiGeorge/velocardiofacial syndrome (DGS/VCFS)-like phenotypes in mouse models, including defects in septation of the outflow tract of the heart and anomalies of pharyngeal arch– derived structures including arteries of the head and neck, laryngeal–tracheal cartilage, and thymus/parathyroid. Wild-type levels of T-box transcription factor (Tbx)1 and RA signaling are required for normal pharyngeal arch artery development. Recent studies have shown that reduction of RA or loss of Tbx1 alters the contribution of second heart field (SHF) progenitor cells to the elongating heart tube. Objective: Here we tested whether Tbx1 and the RA signaling pathway interact during the deployment of the SHF and formation of the mature aortic arch. Methods and Results: Molecular markers of the SHF, neural crest and smooth muscle cells, were analyzed in Raldh2;Tbx1 compound heterozygous mutants. Our results revealed that the SHF and outflow tract develop normally in Raldh2 ؉/؊ ;Tbx1 ؉/؊ embryos. However, we found that decreased levels of RA accelerate the recovery from arterial growth delay observed in Tbx1 ؉/؊ mutant embryos. This compensation coincides with the differentiation of smooth muscle cells in the 4th pharyngeal arch arteries, and is associated with severity of neural crest cell migration defects observed in these mutants. Conclusions: Our data suggest that differences in levels of embryonic RA may contribute to the variability in great artery anomalies observed in DGS/VCFS patients. C ardiovascular development is a complex and ordered process that is regulated by both genetic and epigenetic factors, including dynamic remodeling of the pharyngeal arch arteries (PAAs) and cardiac function. 1 Failure of blood flow during heart development and remodeling leads to cardiovas-cular malformations, including interruption of the aortic arch, double aortic arches, and coarctation of the aorta. 2 Despite the significant prevalence of congenital cardiovascular diseases little is known about molecules that control the subsequent remodeling into a functional vasculature. Cardiovascular defects are a major feature of the DiGeorge/velocardiofacial syndrome (DGS/VCFS), the most common genetic deletion syndrome in humans, with an incidence of 1 in 4000 live births. 3 Most DGS/VCFS patients share a 3-Mb deletion at 22q11.2, whereas 8% harbor a smaller 1.5-Mb deletion in the centromeric half of the 3-Mb region. 3 Extensive genetic analysis in human and mouse indicates that the T-box family gene, TBX1, is the major gene responsible for DGS/VCFS defects (reviewed elsewhere 4). Homozygous Tbx1 mutant mice have craniofacial and …