Over the past several years, the Fibroblast Growth Factor (FGF) and Sprouty signalling pathways have been shown to play a key role in development of dental morphology. Yet despite the extensive investigation of this pathway in tooth development, a critical question has gone unanswered: what are the genetic mechanisms involved in patterning the different elements of the occlusal surface (cusps and crests)? Using 24 rodent species, we have begun to describe 66 unique dental morphologic characters for each species. In addition, we have identified 26 coding and non-coding regions of Fgf3,4,8,9, and 10, conserved among all 24 species. I hypothesize that the interspecific variation of murid dental morphology is governed by the variation of the regulatory genetic code, which works through the orchestration of the variable spatio-temporal expression of the signaling molecules involved in embryonic development. I propose to use the mouse model as well as several in-vitro mouse tooth models to investigate the role of the spatio-temporal variation in expression of FGF and Sprouty signalling pathway members in variation of tooth morphology. The overarching goal of this project is to further investigate the role of genetic regulatory machinery variation as a mechanism of creation of new dental phenotypes. Since such mechanisms may not only yield character states which promote a species'fitness, but sometimes greatly hinder it, as the case with defective phenotypes, understanding the precise genetic mechanisms which drive evolution can further our understanding of the origins of developmental anomalies.

Public Health Relevance

Many head and neck birth defects, such as cleft lip and palate, can significantly decrease the quality of life and are difficult to treat. The etiology of hese defects is complex and requires additional investigation. By understanding the mechanisms of head and neck development, we can devise strategies to better diagnose, prevent, and treat these disorders.

Agency
National Institute of Health (NIH)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DE022482-03
Application #
8628108
Study Section
NIDR Special Grants Review Committee (DSR)
Program Officer
Frieden, Leslie A
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kuang-Hsien Hu, Jimmy; Mushegyan, Vagan; Klein, Ophir D (2014) On the cutting edge of organ renewal: Identification, regulation, and evolution of incisor stem cells. Genesis 52:79-92