Tbx1 regulation of myogenic differentiation in the limb and cranial mesoderm

Abstract

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.

Cranial muscle defects of Pitx2 mutants result from specification defects in the first branchial arch

“…Tbx1 is expressed in both first and second BA at E9.5 and when mutated leads to severe perturbation or absence of both first and second BA muscles (11). Tbx1 also maintains the number of myocytes in the head and limb (35). Interestingly, like Pitx2, expression of Tbx1 follows the onset of myogenic commitment in the limb muscle anlagen but precedes the speciation event in the first BA muscle precursors (15).…”

An eye on the head: the development and evolution of craniofacial muscles

“…Therefore, these genes could act both cell autonomously, as well as non-cell autonomously, to affect muscle development. That these genes also act cell autonomously to control myogenesis in head mesoderm has been supported by conditional knockout studies in mice (Aggarwal et al, 2010;Dastjerdi et al, 2007;Dong et al, 2006;Grifone and Kelly, 2007;Zacharias et al, 2011). However, additional conditional gene ablation studies are needed to assess cell-cell interactions in regulation of muscle cell fates.…”

Pitx2 defines alternate pathways acting through MyoD during limb and somitic myogenesis

“…This could be due to compensation by another factor. Likely candidates include: Pax7, which is expressed in precursors from E11.5 (Kassar-Duchossoy et al, 2005;Relaix et al, 2005); Tbx1, which is initially expressed in dorsal masses of the limbs (Dastjerdi et al, 2007) and reminiscent of residual MyoD expression observed in Pitx2;Myf5(Mrf4) mutants; and, finally, Pitx3, which is expressed after Pitx2 during embryonic myogenesis . Pitx3 does not compensate for loss of Pitx2 towards myogenin or MyoD expression in limbs (see Fig.…”

“…Although this core network has been implicated in all skeletal myogenesis, various studies on hierarchical interactions between MRFs and with upstream transcription factors such as Pax3 suggested that 'wiring' of the myogenesis network is different in trunk, limbs or head muscles (Bajard et al, 2006;Kablar et al, 1999;Kassar-Duchossoy et al, 2004;Sambasivan et al, 2009). In particular, different transcription factors were shown to modulate the core network in these muscles (Dastjerdi et al, 2007;Grifone et al, 2005;Grifone et al, 2007;Mankoo et al, 1999).…”