Cbfa1 is required for epithelial-mesenchymal interactions regulating toothdevelopment in mice

Osteoblasts and odontoblasts, cells that are responsible for the formation of bone and dentin matrices respectively, share several molecular character istics. Recently, Cbfa1 was shown to be a critical transcriptional regulato r of osteoblast differentiation. Mutations in this gene cause cleidocranial dysplasia (CCD), an autosomal dominant disorder in humans and mice charact erized by defective bone formation. CCD also results in dental defects that include supernumerary teeth and delayed eruption of permanent dentition, T he dental abnormalities in CCD suggest an important role for this molecule in the formation of dentition, Here we describe results of studies aimed at understanding the functions of Cbfa1 in tooth formation. RT-PCR and in sit u hybridization analyses show that Cbfa1 has a unique expression pattern in dental mesenchyme from the bud to early bell stages during active epitheli al morphogenesis, Unlike that observed in osteoblast differentiation, Cbfa1 is downregulated in fully differentiated odontoblasts and is surprisingly expressed in ectodermally derived ameloblasts during the maturation phase o f enamel formation. The role of Cbfa1 in tooth morphogenesis is further ill ustrated by the misshapen and severely hypoplastic tooth organs in Cbfa1(-/ -) mice. These tooth organs lacked overt odontoblast and ameloblast differe ntiation and normal dentin and enamel matrices. Epithelial-mesenchymal reco mbinants demonstrate that dental epithelium regulates mesenchymal Cbfa1 exp ression during the bud and cap stages and that these effects are mimicked b y the FGFs but not by the BMPs as shown by our bead implantation assays, We propose that Cbfa1 regulates the expression of molecules in mesenchyme tha t act reciprocally on dental epithelium to control its growth and different iation. Taken together, our data indicate a non-redundant role for Cbfa1 in tooth development that may be distinct from that in bone formation. In odo ntogenesis, Cbfa1 is not involved in the early signaling networks regulatin g tooth initiation and early morphogenesis but regulates key epithelial-mes enchymal interactions that control advancing morphogenesis and histodiffere ntiation of the epithelial enamel organ.