TBX1 is a principal candidate gene for DiGeorge syndrome, a developmental anomaly that affects the heart, thymus, parathyroid, face, and teeth. A mouse model carrying a deletion in a functional region of the Tbx1 gene has been extensively used to study anomalies related to this syndrome. We have used the Tbx1 null mouse to understand the tooth phenotype reported in patients afflicted by DiGeorge syndrome. Because of the early lethality of the Tbx1−/− mice, we used long-term culture techniques that allow the unharmed growth of incisors until their full maturity. All cultured incisors of Tbx1−/− mice were hypoplastic and lacked enamel, while thorough histological examinations demonstrated the complete absence of ameloblasts. The absence of enamel is preceded by a decrease in proliferation of the ameloblast precursor cells and a reduction in amelogenin gene expression. The cervical loop area of the incisor, which contains the niche for the epithelial stem cells, was either severely reduced or completely missing in mutant incisors. In contrast, ectopic expression of Tbx1 was observed in incisors from mice with upregulated Fibroblast Growth Factor signalling and was closely linked to ectopic enamel formation and deposition in these incisors. These results demonstrate that Tbx1 is essential for the maintenance of ameloblast progenitor cells in rodent incisors and that its deletion results in the absence of enamel formation.

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TBX1 encodes a T-box-containing transcription factor, which is thought to be a key player in the aetiology of the DiGeorge and Velocardiofacial syndromes (DGS/VCFS). In addition to defects affecting structures derived from the pharyngeal pouches, these patients exhibit varying degrees of facial dysmorphology and cleft palate. We have analysed the expression of murine Tbx1 during early facial development and found transcripts at sites of known epithelialmesenchymal interaction. In particular, Tbx1 was expressed in epithelium of the early facial processes, including the fronto-nasal, medial and lateral nasal and palatine. Transcripts were also localised to the epithelium of developing tooth germs and hair follicles at several stages during their early development. Together, these expression domains suggest a role for Tbx1 in mediating epithelial-mesenchymal signalling in regions of the developing face, a finding which is consistent with the spectrum of facial deformity encountered amongst subjects affected by DGS/VCFS. KEY WORDS: Tbx1, facial development, tooth morphogenesis, hair follicle morphogenesisThe vertebrate face arises from the interaction of several embryonic cell lineages; ectoderm, endoderm, mesoderm and cranial neural crest. These cell populations construct the face via coordinated growth and differentiation, in the form of a series of simple swellings. Principal amongst these, are the maxillary and mandibular processes of the first pharyngeal arch and the frontonasal process. The complex molecular mechanisms underlying development of these processes are mediated by an array of signalling molecules and transcription factors, generating interaction between the epithelium and underlying mesenchyme (FrancisWest et al., 2003). Any perturbation of these mechanisms can lead to developmental anomalies of the craniofacial region, which can include varying degrees of facial dysmorphology and orofacial clefting.T-box genes encode a large group of transcription factors characterized by a 180-amino-acid DNA-binding domain homologous to the murine Brachyury (T) gene product (Herrmann et al., 1990). TBX1 encodes one member of the vertebrate family of Tbox-containing transcription factors and is thought to be a key player in the aetiology of the DiGeorge and Velocardiofacial syndromes (DGS/VCFS) (Jerome and Papaioannou, 2001, Lindsay et al., 2001, Merscher et al., 2001, Yagi et al., 2003. These syndromes form part of a group of related human dysmorphic disorders that result from deletion or rearrangement of a 3Mb region of chromosome 22q11