Abstract
Transforming growth factor β (TGF-β)/bone morphogenetic protein (BMP) signaling is crucial for regulating epithelial-mesenchymal interaction during organogenesis, and the canonical Smad pathway–mediated TGF-β/BMP signaling plays important roles during development and disease. During tooth development, dental epithelial cells, known as Hertwig's epithelial root sheath (HERS), participate in root formation following crown development. However, the functional significance of HERS in regulating root development remains unknown. In this study we investigated the signaling mechanism of Smad4, the common Smad for TGF-β/BMP signaling, in HERS in regulating root development. Tissue-specific inactivation of Smad4 in HERS results in abnormal enamel and dentin formation in K14-Cre;Smad4fl/fl mice. HERS enlarges but cannot elongate to guide root development without Smad4. At the molecular level, Smad4-mediated TGF-β/BMP signaling is required for Shh expression in HERS and Nfic (nuclear factor Ic) expression in the cranial neural crest (CNC)-derived dental mesenchyme. Nfic is crucial for root development, and loss of Nfic results in a CNC-derived dentin defect similar to the one of K14-Cre;Smad4fl/fl mice. Significantly, we show that ectopic Shh induces Nfic expression in dental mesenchyme and partially rescues root development in K14-Cre;Smad4fl/fl mice. Taken together, our study has revealed an important signaling mechanism in which TGF-β/BMP signaling relies on a Smad-dependent mechanism in regulating Nfic expression via Shh signaling to control root development. The interaction between HERS and the CNC-derived dental mesenchyme may guide the size, shape, and number of tooth roots. © 2010 American Society for Bone and Mineral Research.
Highlights
Tooth crown formation is a multistep process that is mediated through a series of epithelial-mesenchymal interactions.[1,22] bone morphogenetic protein (BMP), sonic hedgehog (Shh), Wnt, and fibroblast growth factors (FGFs) are expressed in the developing root, the molecular regulatory mechanism of root development remains unknown
The transition from dental cervical loop to Hertwig’s epithelial root sheath (HERS) is generally regarded as the beginning of root formation.[38,39] the functional mechanism of HERS in guiding root development is still unclear.[38,39,40,41] In this study we investigated the functional significance of transforming growth factor b (TGF-b)/BMP signaling in regulating the fate of HERS cells and epithelial-mesenchymal interaction during root development
TGF-b/BMP signaling has been shown to function in the initiation of tooth and root development.[4,13,14,18] Bmp2, -3, -4, and -7 are detected during root development, and inhibition of BMP signaling in K14-Noggin mice results in a severe rootdevelopment defect.[42,43] Smad4, the central mediator for the canonical TGF-b/BMP signaling pathway, plays a crucial role in regulating tooth development.[31]. In order to investigate the functional significance of TGF-b/BMP signaling in dental epithelial cells during root development, we used K14Cre;Smad4fl/fl mice lacking Smad4 expression in dental epithelial cells
Summary
Mammalian ectodermal cells undergo complex reciprocal interactions with underlying mesenchymal cells to form a variety of appendages, including teeth, hair follicles, and mammary glands.[1,2,3] The tooth organ is an excellent model for studies of heterotypic tissue interactions and the formation of unique dental structures.[1,4,5,6,7,8,9,10,11,12] Tooth crown formation is controlled by many cytokines and transcription factors that regulate critical gene expression during tooth development.[4,13,14] Compared with the study of crown formation, we have limited information on the molecular regulatory mechanism of root development.Following crown development, inner enamel epithelium (IEE) and outer enamel epithelium (OEE) form a bilayered epithelial structure termed Hertwig’s epithelial root sheath (HERS) that migrates apically and participates in root formation and the completion of tooth organ development. HERS breaks up into epithelial rests and cords, allowing dental follicle cells to come in contact with the outer surface of the root during dentin and cementum formation. This strategic position suggests an important role for HERS during critical interactions between dental epithelium and mesenchyme.[15,16,17]. Smad is a central mediator of the canonical TGF-b signaling pathway
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