Downregulation of FGF Signaling by Spry4 Overexpression Leads to Shape Impairment, Enamel Irregularities, and Delayed Signaling Center Formation in the Mouse Molar

Abstract

FGF 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.

The role of O‐GlcNAcylation mediated by OGT during tooth development

“…As we hypothesized from the previous reports (Gritli‐Linde et al, 2002; Li et al, 2018; Liu et al, 2008; Marangoni et al, 2019; Xiong et al, 2019) and our functional evaluation using an in vitro cultivation, 3 weeks calcified teeth showed the altered morphogenesis with smaller size, fewer cusps and disrupted pattern of enamel and dentin arrangements in OGT inhibited teeth (Figure 5). This altered morphogenesis of teeth would be related with the alterations in functional regulations including Fgf4, Shh, and Wnt signalings (Figure 3).…”

“…This altered morphogenesis of teeth would be related with the alterations in functional regulations including Fgf4, Shh, and Wnt signalings (Figure 3). Downregulation of Fgf signaling induced enamel irregularities, delayed signaling center formation, and smaller teeth (Marangoni et al, 2019). This was evident in OGT‐inhibited kidney calcified teeth (Figures 3 and 5).…”

Human iPSC Derived Enamel Organoid Guided by Single-Cell Atlas of Human Tooth Development

“…Our analysis showed that BMP4 signaling is critical during the early stages of both the OE to DE and DE to OEE transition, suggesting that loss of BMP4 may lead to agenesis by disrupting these transitions. In other studies, disruption of FGF signaling leads to enamel irregularities (Marangoni et al, 2019). Using AI-based protein design, we now revealed that FGF signaling is essential at the point of ameloblast maturation, suggesting that these irregularities are a result of failure of ameloblasts to mature.…”

Molecular and cellular mechanisms of tooth development, homeostasis and repair

“…Loss of Spry2 and Spry4 results in persistent expression of FGFs during early tooth development, inducing ectopic molar formation in the normally toothless region called the diastema (Klein et al, 2006). Conversely, epithelial overexpression of Spry4 represses FGF signaling, resulting in delayed development of the mouse molar (Marangoni et al, 2019).…”