Role of TBX1 in human del22q11.2 syndrome

The T-box transcription factor Tbx1 has been implicated in DiGeorge syndrome, the most frequent syndrome due to a chromosomal deletion. Gene inactivation of Tbx1 in mice results in craniofacial and branchial arch defects, including myogenic defects in the first and second branchial arches. A T-box binding site has been identified in the Xenopus Myf5 promoter, and in other species, T-box genes have been implicated in myogenic fate. Here we analyze Tbx1 expression in the developing chick embryo relating its expression to the onset of myogenic differentiation and cellular fate within the craniofacial mesoderm. We show that Tbx1 is expressed before capsulin, the first known marker of branchial arch 1 and 2 muscles. We also show that, as in the mouse, Tbx1 is expressed in endothelial cells, another mesodermal derivative, and, therefore, Tbx1 alone cannot specify the myogenic lineage. In addition, Tbx1 expression was identified in both chick and mouse limb myogenic cells, initially being restricted to the dorsal muscle mass, but in contrast, to the head, here Tbx1 is expressed after the onset of myogenic commitment. Functional studies revealed that loss of Tbx1 function reduces the number of myocytes in the head and limb, whereas increasing Tbx1 activity has the converse effect. Finally, analysis of the Tbx1-mesoderm-specific knockout mouse demonstrated the cell autonomous requirement for Tbx1 during myocyte development in the cranial mesoderm. Developmental Dynamics 236:353-363, 2007.

Section: Introductionmentioning

confidence: 99%

Tbx1 regulation of myogenic differentiation in the limb and cranial mesoderm

Dastjerdi

Robson

Walker

et al. 2006

“…However, approximately 10% of DGS/ VCFS cases have no detectable deletion of chromosome 22q11 or 10p13 (Gong et al, 2001;Conti et al, 2003). Screens for point mutations of TBX1 in such cases have been largely negative, but three Japanese cases have been described (Yagi et al, 2003). Thus, the mouse chromosome deletion gives Tbx1 haploinsufficiency in the context of hemizygosity of 21 genes and is the model most representative of disease in most patients.…”

Section: Introductionmentioning

confidence: 99%

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

Roberts¹,

Ivins²,

James³

et al. 2005

105

Both Tbx1 and retinoic acid (RA) are key players in embryonic pharyngeal development; loss of Tbx1 produces DiGeorge syndrome-like phenotypes in mouse models as does disruption of retinoic acid homeostasis. We have demonstrated that perturbation of retinoic acid levels in the avian embryo produces altered Tbx1 expression. In vitamin A-deficient quails, which lack endogenous retinoic acid, Tbx1 expression patterns were disrupted early in development and expression was subsequently lost in all tissues. "Gain-of-function" experiments where RA-soaked beads were grafted into the pharyngeal region produced localized down-regulation of Tbx1 expression. In these embryos, analysis of Shh and Foxa2, upstream control factors for Tbx1, suggested that the effect of RA was independent of this regulatory pathway. Real-time polymerase chain reaction analysis of retinoic acid-treated P19 cells showed a dosedependent repression of Tbx1 by retinoic acid. Repression of Tbx1 transcript levels was first evident after 8 -12 hr in culture in the presence of retinoic acid, and to achieve the highest levels of repression, de novo protein synthesis was required. Developmental Dynamics 232:928 -938, 2005.

“…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.…”

Section: Utility Of Mlc1v-egfp Embryos For Studies Of Cardiac and Cramentioning

confidence: 99%

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

Smith¹,

Ataliotis²,

Kotecha³

et al. 2005

Many details of cardiac chamber morphogenesis could be revealed if muscle fiber development could be visualized directly within the hearts of living vertebrate embryos. To achieve this end, we have used the active promoter of the MLC1v gene to drive expression of green fluorescent protein (GFP) in the developing tadpole heart. By using a line of Xenopus laevis frogs transgenic for the MLC1v-EGFP reporter, we have observed regionalized patterns of muscle formation within the ventricular chamber and maturation of the atrial chambers, from the onset of chamber formation through to the adult frog. In f1 generation MLC1v-EGFP animals, promoter activity is first detected within the looping heart tube and delineates the forming ventricular chamber and proximal outflow tract throughout their development.