DiGeorge syndrome is a spectrum of congenital malformations including craniofacial defects, thymus and thyroid/parathyroid hypoplasia, interrupted aortic arch, ventricle septation defects, and outflow tract malformations such as persistent truncus arteriosus and Tetralogy of Fallot. In humans, DiGeorge syndrome is usually caused by heterozygous deletion of the q11.2 region of chromosome 22. Among the many genes in this region, Tbx1 is generally thought to be of particular importance in the etiology of DiGeorge syndrome, in part because mutation of the Tbx1 gene in mouse replicates most of the phenotypes seen in human infants. In mice, mutation of certain other genes also results in DiGeorge syndrome defects, and in every case these have been shown to interact at the molecular level with Tbx1. In this thesis, we describe for the first time that conditional deletion in endothelial cells of a gene unrelated to Tbx1 also causes DiGeorge syndrome malformations in mice. We propose that vascular deficiency can lead to or be a cause of DiGeorge syndrome.

In second part of the thesis, we addressed the requirement for TGFβ signaling in the formation and maintenance of the vascular matrix. We employed lineage-specific mutation of the type II TGFβ receptor gene ( Tgfbr2) in vascular smooth muscle precursors in mice. In mesoderm-derived smooth muscle, absence of TGFβ receptor function resulted in a poorly organized vascular elastic matrix in late-stage embryos which was prone to dilation and aneurysm. This defect represents a failure to initiate formation of the elastic matrix, rather than a failure to maintain a preexisting matrix. In mutant tissue, lysyl oxidase expression was substantially reduced, which may contribute to the observed pathology.