D'Souza R N, Aberg T, Gaikwad J, Cavender A, Owen M, Karsenty G, Thesleff I
Developmental Biology Program, Institute of Biotechnology, Viikki Biocenter, FIN-00014 University of Helsinki, Finland.
Development. 1999 Jul;126(13):2911-20. doi: 10.1242/dev.126.13.2911.
Osteoblasts and odontoblasts, cells that are responsible for the formation of bone and dentin matrices respectively, share several molecular characteristics. Recently, Cbfa1 was shown to be a critical transcriptional regulator of osteoblast differentiation. Mutations in this gene cause cleidocranial dysplasia (CCD), an autosomal dominant disorder in humans and mice characterized by defective bone formation. CCD also results in dental defects that include supernumerary teeth and delayed eruption of permanent dentition. The 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 situ hybridization analyses show that Cbfa1 has a unique expression pattern in dental mesenchyme from the bud to early bell stages during active epithelial 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 of enamel formation. The role of Cbfa1 in tooth morphogenesis is further illustrated by the misshapen and severely hypoplastic tooth organs in Cbfa1-/- mice. These tooth organs lacked overt odontoblast and ameloblast differentiation and normal dentin and enamel matrices. Epithelial-mesenchymal recombinants demonstrate that dental epithelium regulates mesenchymal Cbfa1 expression during the bud and cap stages and that these effects are mimicked by 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 that act reciprocally on dental epithelium to control its growth and differentiation. Taken together, our data indicate a non-redundant role for Cbfa1 in tooth development that may be distinct from that in bone formation. In odontogenesis, Cbfa1 is not involved in the early signaling networks regulating tooth initiation and early morphogenesis but regulates key epithelial-mesenchymal interactions that control advancing morphogenesis and histodifferentiation of the epithelial enamel organ.
成骨细胞和成牙本质细胞分别负责骨和牙本质基质的形成，它们具有一些共同的分子特征。最近研究表明，Cbfa1是成骨细胞分化的关键转录调节因子。该基因的突变会导致锁骨颅骨发育不全（CCD），这是一种人类和小鼠的常染色体显性疾病，其特征是骨形成缺陷。CCD还会导致牙齿缺陷，包括多生牙和恒牙萌出延迟。CCD中的牙齿异常表明该分子在牙列形成中起重要作用。在此，我们描述了旨在了解Cbfa1在牙齿形成中功能的研究结果。逆转录聚合酶链反应（RT-PCR）和原位杂交分析表明，在活跃的上皮形态发生过程中，从芽期到早期钟状期，Cbfa1在牙间充质中具有独特的表达模式。与在成骨细胞分化中观察到的情况不同，Cbfa1在完全分化的成牙本质细胞中表达下调，并且在釉质形成成熟阶段在外胚层来源的成釉细胞中意外表达。Cbfa1-/-小鼠中畸形且严重发育不全的牙器官进一步说明了Cbfa1在牙齿形态发生中的作用。这些牙器官缺乏明显的成牙本质细胞和成釉细胞分化以及正常的牙本质和釉质基质。上皮-间充质重组实验表明，在芽期和帽状期，牙上皮调节间充质Cbfa1的表达，并且如我们的珠子植入实验所示，这些作用可被成纤维细胞生长因子（FGFs）模拟，但不能被骨形态发生蛋白（BMPs）模拟。我们提出，Cbfa1调节间充质中分子的表达，这些分子反过来作用于牙上皮以控制其生长和分化。综上所述，我们的数据表明Cbfa1在牙齿发育中具有非冗余作用，这可能与在骨形成中的作用不同。在牙发生过程中，Cbfa1不参与调节牙齿起始和早期形态发生的早期信号网络，而是调节关键的上皮-间充质相互作用，这些相互作用控制上皮釉器的形态发生进展和组织分化。
