Tbx1, a DiGeorge Syndrome Candidate Gene, Is Regulated by Sonic Hedgehog during Pharyngeal Arch Development

Abstract

Appropriate interactions between the epithelium and adjacent neural crest-derived mesenchyme are necessary for normal pharyngeal arch development. Disruption of pharyngeal arch development in humans underlies many of the craniofacial defects observed in the 22q11.2 deletion syndrome (del22q11), but the genes responsible remain unknown. Tbx1 is a T-box transcription factor that lies in the 22q11.2 locus. Tbx1 transcripts were found to be localized to the pharyngeal endoderm and the mesodermal core of the pharyngeal arches, but were not present in the neural crest-derived mesenchyme of the pharyngeal arches. Sonic hedgehog (Shh) is also expressed in the pharyngeal arches and is necessary for normal craniofacial development. We found that Tbx1 expression was dependent upon Shh signaling in mouse embryos, consistent with their overlapping expression in the pharyngeal arches. Furthermore, Shh was sufficient to induce Tbx1 expression when misexpressed in selected regions of chick embryos. These studies reveal a Shh-mediated pathway that regulates Tbx1 during pharyngeal arch development.

Tbx1 regulation of myogenic differentiation in the limb and cranial mesoderm

“…Tbx1 transcripts were also detectable in the otocyst and endoderm as previously reported ( Fig. 2A,B, F,G, K; Garg et al, 2001), and undifferentiated nonmyogenic mesoderm (compare B,G with C-E and H-J, K with L,N; see Garg et al, 2001, Brown et al, 2004 for equivalent mouse expression). Tbx1 is not expressed in the extraocular muscles; compare Figure 2K with 2L,N, which show the medial rectus muscle, an extraocular muscle (arrowed).…”

“…1A, black arrows) and a band of mesenchyme ventral to the otic pit (Fig. 1A, also see Garg et al, 2001). The extraocular eye muscle, the lateral rectus, which arises adjacent to the hindbrain and migrates to its final destination was also found to express Tbx1 (position indicated by white arrow in Fig.…”

“…They were incubated at 37 Ϯ 1°C and were staged according to Hamburger and Hamilton (1951). Tbx1 Ϫ/Ϫ mutants (as described by Lindsay et al, 2001;Garg et al, 2001) were maintained on a mixed C57Bl/6 background. Embryos were obtained from time-mated females, and they were genotyped by analysis of genomic DNA from tail snips.…”

“…Tbx1 is expressed in the endoderm and mesoderm of the branchial arches, and this expression pattern is conserved between mice, chicks, Xenopus, zebrafish, and lamprey (Chapman et al, 1996;Garg et al, 2001;Lindsay et al, 2001;Sauka-Spengler et al, 2002;Kochilas et al, 2003;Piotrowski et al, 2003;Ataliotis et al, 2005). In addition, expression of Tbx1 is also found in the otic vesicle and surrounding mesenchyme, where it is necessary for morphogenesis of the inner ear and the ultimate development of the cochlea and vestibular apparatus (Vitelli et al, 2003;Raft et al, 2004).…”

“…In addition, expression of Tbx1 is also found in the otic vesicle and surrounding mesenchyme, where it is necessary for morphogenesis of the inner ear and the ultimate development of the cochlea and vestibular apparatus (Vitelli et al, 2003;Raft et al, 2004). In the mouse, expression has also been observed in the tooth bud and a proximal domain of expression in the developing limb bud has been noted (Garg et al, 2001).…”