TBX1 Is Responsible for Cardiovascular Defects in Velo-Cardio-Facial/DiGeorge Syndrome

Abstract

Velo-cardio-facial syndrome (VCFS)/DiGeorge syndrome (DGS) is a human disorder characterized by a number of phenotypic features including cardiovascular defects. Most VCFS/DGS patients are hemizygous for a 1.5-3.0 Mb region of 22q11. To investigate the etiology of this disorder, we used a cre-loxP strategy to generate mice that are hemizygous for a 1.5 Mb deletion corresponding to that on 22q11. These mice exhibit significant perinatal lethality and have conotruncal and parathyroid defects. The conotruncal defects can be partially rescued by a human BAC containing the TBX1 gene. Mice heterozygous for a null mutation in Tbx1 develop conotruncal defects. These results together with the expression patterns of Tbx1 suggest a major role for this gene in the molecular etiology of VCFS/DGS.

Tbx1 regulation of myogenic differentiation in the limb and cranial mesoderm

“…However, equally it could be taken as evidence that Tbx1 may have a proliferative role in either the developing myogenic cells or their mesodermal precursors. In support of this hypothesis is that, in the Tbx1 null mouse, a unifying theme is the reduction in cell number in Tbx1-expressing tissues (Lindsay et al, 2001;Merscher et al, 2001;Vitelli et al, 2003;Zhang et al, 2006). In the endoderm and mesoderm, including the secondary heart field, this reduction in cell number is linked to a decrease in cell proliferation (Xu et al, 2004Zhang et al, 2006).…”

Retinoic acid down‐regulates Tbx1 expression in vivo and in vitro

“…At embryonic day (E) 18.5, these animals displayed characteristic DGS/VCFS-like aortic arch defects, resulting from aplasia or hypoplasia of the fourth aortic arch artery earlier in development. Rescue of the phenotype was accomplished by genetic complementation with PACs or human BACs containing Tbx1 (Lindsay et al, 1999(Lindsay et al, , 2001Merscher et al, 2001). Null mutations of Tbx1 in the heterozygous state recapitulated the aortic arch anomalies seen in animals with large hemizygous chromosomal deletions.…”

“…Null mutations of Tbx1 in the heterozygous state recapitulated the aortic arch anomalies seen in animals with large hemizygous chromosomal deletions. Homozygous null animals at E18.5 displayed defects including the majority of common DGS/VCFS features arising from the earlier loss of caudal pharyngeal structures (Jerome and Papaioannou, 2001;Lindsay et al, 2001;Merscher et al, 2001). Recently, the gene for the van gogh zebrafish mutant, which also has DGS-like defects, has been cloned and identified as the zebrafish homologue of Tbx1 (Kochilas et al, 2003;Piotrowski et al, 2003).…”

The MLC1v gene provides a transgenic marker of myocardium formation within developing chambers of the Xenopus heart

“…Indeed, MLC1v-EGFP Xenopus embryos have been used as part of a larger investigation of the role of the T-box protein, Tbx1, in controlling these processes (Ataliotis et al, 2005). Tbx1 is expressed throughout the mesoderm and endoderm of each visceral arch in all vertebrates and, when defective, is responsible for many of the disease malformations that occur in the human chromosome 22q11.2 deletion, DiGeorge syndrome (Jerome and Papaioannou, 2001;Lindsay et al, 2001;Merscher et al, 2001;Yagi et al, 2003;Baldini, 2004). DiGeorge patients exhibit a spectrum of malformations, including conotruncal outflow tract and chamber septation defects in the heart, thymic hypoplasia, hypoparathyroidism, and facial abnormalities such as cleft palate.…”