Despite the advances made in identifying the signaling pathways in tooth germ and crown morphogenesis, the precise molecular events leading to root formation are largely unknown. Since dentin forms the bulk of the root, such knowledge is critical for exploring how pulpal cells respond to injury by forming a reparative dentin matrix and for developing predictable therapies for dentin-pulp complex repair. The current belief is that root development is initiated from HERS (Hertwig's Epithelial Root Sheath), but amelogenesis imperfecta patients exhibit no apparent root defects. Our recent data showed that the target deletion of Bmpr1a in epithelium by keratin 5 Cre induced at E14.5 leads to severe enamel defects but showed no apparent root dentin phenotype, suggesting that molecules originating from mesenchymal cells may play critical roles during root formation. The root dentinogenesis model offers a practical means of studying how odontoblast differentiation is regulated at the molecular level. In this study, we will perform a series of experiments to test the hypothesis that BMPR1A signaling originating from pulp/odontoblast cells controls root formation via a novel NFIC-OSX-?-catenin-DSPP signaling pathway. We have proposed three Aims.
In specific Aim 1 we will test the hypothesis that OSX is a key downstream molecule of BMPR1A. To test this hypothesis, we will use the 3.2 Col 1ERTM-Cre (induced by injection of Tamoxifen) to determine the degree to which re-expression of Osx1 can rescue the abnormal root phenotype in Bmpr1a cKO.
In Specific Aim 2 we will test the hypothesis that OSX controls root dentinogenesis through (i) the inhibition of cell proliferation and (ii) the acceleration of cll differentiation via the inhibition of ?-catenin and upregulation of DSPP.
In Specific Aim 3 we will test the hypothesis that NFIC, an essential transcriptional factor for root dentinogenesis, is a ke downstream molecule of BMP, which controls root dentinogenesis via OSX. To test this hypothesis, we will re-express Nfic in the Bmpr1a cKO osteoblasts to determine the degree to which Nfic can rescue the abnormal root phenotype. We will also re-express Osx in the Nfic KO odontoblasts to determine the degree to which re-expression of Osx can rescue the abnormal root phenotype. Upon completion of this project in an understudied area, we will provide new mechanistic insights into the role of these signaling molecules from mesenchymal cells during root formation. This valuable information will not only challenge the current dogma (induction of root signal is from HERS) but will also be applied to the development of new bioactive restorative therapies aimed at restoring the integrity of the dentin-pulp complex after injury.
Patients with trauma leading to tooth fracture or genetic diseases require tooth replacement. This research proposal will explore a novel way to facilitate root regeneration by understanding how root dentin is formed. Specifically, we plan to use genetic engineered mouse models to clarify roles of an emerging signaling pathway during postnatal root formation. The completion of this project will have a broad impact on dentistry (clinical translation studies), developmental and stem cell research areas, as well as the way we teach future dental/medical students.
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|Cao, Zhengguo; Liu, Rubing; Zhang, Hua et al. (2015) Osterix controls cementoblast differentiation through downregulation of Wnt-signaling via enhancing DKK1 expression. Int J Biol Sci 11:335-44|
|Zhang, Hua; Jiang, Yong; Qin, Chunlin et al. (2015) Essential role of osterix for tooth root but not crown dentin formation. J Bone Miner Res 30:742-6|
|Ren, Yinshi; Han, Xianglong; Ho, Sunita P et al. (2015) Removal of SOST or blocking its product sclerostin rescues defects in the periodontitis mouse model. FASEB J 29:2702-11|
|Feng, J Q; Zhang, H; Qin, C (2015) Letter to the Editor, "Osterix Regulates Tooth Root Formation in a Site-specific Manner". J Dent Res 94:1326|
|Jing, Y; Zhou, X; Han, X et al. (2015) Chondrocytes Directly Transform into Bone Cells in Mandibular Condyle Growth. J Dent Res 94:1668-75|
|Hinton, Robert J; Jing, Junjun; Feng, Jian Q (2015) Genetic Influences on Temporomandibular Joint Development and Growth. Curr Top Dev Biol 115:85-109|
|Jing, J; Hinton, R J; Jing, Y et al. (2014) Osterix couples chondrogenesis and osteogenesis in post-natal condylar growth. J Dent Res 93:1014-21|
|Lin, Shu-Xian; Zhang, Qi; Zhang, Hua et al. (2014) Nucleus-targeted Dmp1 transgene fails to rescue dental defects in Dmp1 null mice. Int J Oral Sci 6:133-41|
|Lin, Shuxian; Zhang, Qi; Cao, Zhengguo et al. (2014) Constitutive nuclear expression of dentin matrix protein 1 fails to rescue the Dmp1-null phenotype. J Biol Chem 289:21533-43|
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