Role of CPNE7 during Amelogenesis and Odontogenesis

Abstract

Odontogenesis is a complex physiological process of tooth development, which involves both ectodermal and mesenchymal components, being the key elements in the development of teeth. In order for the tooth to form, an interactive mechanism between these heterotypic cellular populations is required. Based on the concept of epithelial-mesenchymal interactions during odontogenesis, Copine-7 (Cpne7), a dental epithelium-derived factor, was identified as a diffusing signaling molecule for regulation the differentiation of mesenchymal cells of dental or non-dental origin into odontoblasts in the previous study. However, the mechanisms involved in the translocation of Cpne7 from preameloblasts to preodontoblasts and the functions of Cpne7 during odontogenesis have not yet been clarified. The results from part I study provide confirmation for both the mRNA and protein expression of Dspp in differentiating ameloblasts and its expression pattern is similar to that of Cpne7 during ameloblast differentiation. Moreover, GEO profiles indicate that there is a close correlation between Cpne7 and Dspp expression in various normal human tissues. Cpne7 overexpression promotes Dspp expression, whereas Dspp expression is downregulated by Cpne7 inactivation in early amelogenesis. Mechanism of such regulation is confirmed by findings that CPNE7 binds to the Dspp promoter region and regulates its transcription. Taken together, these findings suggest that Dspp is synthesized in dental epithelial cells by the control of CPNE7 and its transient expression occurs in early ameloblasts. The results from part II study strongly suggest a mechanism in which Cpne7 is internalized into preodontoblasts and transported to the nucleus, which implied possible strategies to regulate odontoblast differentiation. Cpne7 acts as a ligand and bounds to its receptor, nucleolin in lipid rafts, and is internalized via caveolae-mediated endocytosis. The Cpne7-nucleolin complex is then translocated to the nucleus of preodontoblasts. Cpne7 increases the formation of primary cilia affecting the expression of Kif3a and Ift88, cilium components. Ift88 promotes up-regulation of Dspp expression. Taken together, I propose that the existence of a Cpne7-nucleolin complex-primary cilia-Dspp pathway during early odontoblast differentiation. Collectively, these studies provide the evidence for the roles and underlying mechanisms of Cpne7 on Dspp expression during early amelogenesis and ciliogenesis of mesenchymal stem cells during dentinogenesis.