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Early perturbation of Wnt signaling reveals patterning and invagination-evagination control points in molar tooth development

  • Author(s): Kim, Rebecca Yewon
  • Advisor(s): Bush, Jeffrey O
  • et al.
Abstract

The developing tooth offers a model for the study of ectodermal appendage organogenesis. The signaling networks that regulate tooth development have been intensively investigated, but how cell biological responses to signaling pathways regulate dental morphogenesis remains an open question. One of the challenges has been the lack of tools to study the role of the odontogenic signaling pathways in specific time and space. This dissertation investigates the role of Wnt/β-catenin pathway during the earliest stages of tooth development through utilizing a unique combination of genetic tools that the our has been previously identified.

Tooth formation involves an orchestration of different signaling pathways both within the oral epithelium and between the epithelium and the underlying mesenchyme. Previous studies of the Wnt/β-catenin pathway have shown that tooth formation is partly inhibited in loss-of-function mutants, and gain-of-function mutants have perturbed tooth morphology, such as hyper-calcification of existing dentition and formation of supernumerary teeth. However, the stage at which Wnt signaling is first important in tooth formation has not been elucidated.

Our lab previously identified Fgf8 as one of the earliest markers of tooth development in mouse. Building on this knowledge, I induced Fgf8-promoter-driven and therefore early deletion of β-catenin in molar epithelium and discovered that loss of Wnt/β-catenin signaling completely deletes the molar tooth, demonstrating that this pathway is central to the earliest stages of tooth formation. Early expression of a dominant-active β-catenin protein also perturbs tooth formation, producing a large domed evagination at early stages and supernumerary teeth later on. The early evaginations are associated with premature mesenchymal condensation marker, and are reduced by inhibition of condensation-associated collagen synthesis. This dissertation proposes that invagination versus evagination morphogenesis is regulated by the relative timing of epithelial versus mesenchymal cell convergence regulated by canonical Wnt signaling. Together, these studies reveal new aspects of Wnt/β-catenin signaling in tooth formation and epithelial morphogenesis more broadly.

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