The Wnt signaling pathway plays a central role in embryonic development and adult tissue homeostasis. Wnt signaling can be categorized into canonical and non-canonical, depending on which effectors relay signals in Wnt-responsive cells. The canonical Wnt signaling pathway is mediated by -catenin, whereas non-canonical pathways are -catenin-independent. An important unsolved question in developmental biology is how canonical Wnt signaling regulates early stages of tooth development (odontogenesis). One of the major limitations in uncovering the role of Wnt signaling in tooth development has been a lack of specific markers for dental progenitor cells. Previous studies utilized general activation and ablation of Wnt signaling in oral epithelial and mesenchymal tissues to study how it regulates odontogenesis. However, this broad targeting complicates our understanding of the relationship between Wnt signaling and odontogenesis. We have recently discovered that transient expression of Fgf8 at E11.5 marks dental epithelial progenitor cells (DEPCs). Building on this finding, I activated Wnt signaling specifically in DEPCs, and in contrast to the normally occurring invagination of the epithelium into the underlying dental mesenchyme, I found that the epithelium evaginated into the oral cavity. This observation led me to hypothesize that canonical Wnt signaling regulates the position of DEPCs along the superior-inferior axis. Through this project, I will further explore the role of canonical Wnt signaling during tooth development by assessing the Wnt- responsiveness of DEPCs, and by taking gain- and loss-of-function approaches to evaluate the regulatory role of Wnt signaling in tooth development from the molecular to the organ level. Understanding the mechanism underlying invagination of dental epithelium, as well as the relationship between the migration pattern of DEPCs and the resulting dental morphology, is crucial for understanding the mechanics of tooth development. Thus, this study can provide significant insight into basic tooth biology as well as for regenerative medicine, such as therapeutic dental tissue engineering.

Public Health Relevance

Common avenues to restore missing teeth (i.e. fixed dentures and dental implants) require preparation of adjacent healthy teeth, and these can fail due to limited osseointegration. Due to the limitations of the current therapies, there is a strong need for biological replacement of missing teeth. This project will address the role of canonical Wnt signaling in tooth development, thus providing insight for regenerative dentistry, such as dental tissue bioengineering.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZDE1)
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Frieden, Leslie A
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University of California San Francisco
Schools of Dentistry/Oral Hygn
San Francisco
United States
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Kim, Rebecca; Green, Jeremy B A; Klein, Ophir D (2017) From snapshots to movies: Understanding early tooth development in four dimensions. Dev Dyn 246:442-450
Goodwin, Alice F; Kim, Rebecca; Bush, Jeffrey O et al. (2015) From Bench to Bedside and Back: Improving Diagnosis and Treatment of Craniofacial Malformations Utilizing Animal Models. Curr Top Dev Biol 115:459-92