Abstract
ABSTRACTFGF signaling plays a critical role in tooth development, and mutations in modulators of this pathway produce a number of striking phenotypes. However, many aspects of the role of the FGF pathway in regulating the morphological features and the mineral quality of the dentition remain unknown. Here, we used transgenic mice overexpressing the FGF negative feedback regulator Sprouty4 under the epithelial keratin 14 promoter (K14‐Spry4) to achieve downregulation of signaling in the epithelium. This led to highly penetrant defects affecting both cusp morphology and the enamel layer. We characterized the phenotype of erupted molars, identified a developmental delay in K14‐Spry4 transgenic embryos, and linked this with changes in the tooth developmental sequence. These data further delineate the role of FGF signaling in the development of the dentition and implicate the pathway in the regulation of tooth mineralization. © 2019 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
Teeth develop through a series of signaling interactions between dental epithelium and the underlying mesenchyme
Sprouty (Spry) genes were first identified as inhibitors of signaling through FGF receptors (FGFRs) in tracheal morphogenesis in Drosophila, and soon after these findings were extended to the mouse.[15]. Four Sprouty orthologs are found in the Mus musculus genome,(16) and Spry1, Spry2, and Spry4 are expressed during tooth development.[7]. Their expression is induced upon growth factor stimulation, and the protein products inhibit FGFR‐mediated activation of the ERK‐MAPK signaling pathway.[17]. In the mouse, Spry2 and Spry4 prevent the development of supernumerary teeth,(7) and Spry1, Spry2, and Spry4 are required for correct molar
In the course of tooth development Spry4 is normally expressed in the dental mesenchyme,(7) the K14‐Spry4 transgene is expressed throughout the oral epithelium, including the dental epithelium
Summary
Teeth develop through a series of signaling interactions between dental epithelium and the underlying mesenchyme. To further investigate the roles of the FGF signaling pathway in odontogenesis, we utilized a transgenic mouse line (K14‐Spry4) in which the expression of mouse Spry is driven in the epithelium of many ectodermal organs under the control of the human keratin‐14 promoter. This line was designed to attenuate epithelial FGF signaling. Histological analyses of the developing molar germs highlight a developmental delay that affects the formation of the tooth signaling center known as the primary enamel knot (pEK) These findings further establish FGF signaling as a critical regulator of enamel mineralization and confirm its role in controlling tooth shape
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