Expression and function of FGFs-4, -8, and -9 suggest functional redundancy and repetitive use as epithelial signals during tooth morphogenesis

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Abstract
To elucidate the roles of fibroblast growth factors (FGF) in the regulation of tooth morphogenesis we have analyzed the expression patterns of Fgf-4, -8, and -9 in the developing mouse molar and incisor tooth germs from initiation to completion of morphogenesis by in situ hybridization analysis. The expression of these Fgfs was confined to dental epithelial cells at stages when epithelial-mesenchymal signaling regulates critical steps of tooth morphogenesis. Fgf-8 and Fgf-9 mRNAs were present in the oral epithelium of the first branchial arch at E10 and 1 day later expression became more restricted to the area of presumptive dental epithelium and persisted there until the start of epithelial budding. Fgf-8 mRNAs were not detected later in the developing tooth. Fgf-4 and Fgf-9 expression was upregulated in the primary enamel knot, which is a putative signaling center regulating tooth shape. Subsequently, Fgf-4 and Fgf-9 were expressed in the secondary enamel knots at the sites of tooth cusps. Fgf-9 expression spread from the primary enamel knot within the inner enamel epithelium where it remained until E18. In the continuously growing incisors Fgf-9 expression persisted in the epithelium of the cervical loops. The effects of FGFs were analyzed on the expression of the homeobox-containing transcription factors Msx-1 and Msx-2, which are associated with tissue interactions and regulated by the dental epithelium. Locally applied FGF-4, -8, and -9 stimulated intensely the expression of Msx-1 but not Msx-2 in the isolated dental mesenchyme. We suggest that the three FGFs act as epithelial signals mediating inductive interactions between dental epithelium and mesenchyme during several successive stages of tooth formation. This data suggest roles for FGF-8 and FGF-9 during initiation of tooth development, and for FGF-4 and FGF-9 during regulation of tooth shape. FGF-9 may also be involved in differentiation of odontoblasts. The coexpression of Fgfs with other signaling molecules including Shh and several Bmps and their partly similar effects suggest that the FGFs participate in the signaling networks during odontogenesis. Dev. Dyn. 1998;211:256–268.