Genetic and molecular studies in humans and mice indicate that Osf2/Cbfal is a critical transcriptional regulator of bone formation. Heterozygous mutants in Osf2/Cbfa1 cause cleidocranial dysplasia (CCD), an inherited disorder in humans and mice characterized by skeletal defects. Mice lacking a functional Cbfa1 gene die at birth and lack bone. CCD also results in supernumerary teeth, defects in tooth form and structure and delayed eruption. Analysis of the expression of Osf2/Cbfal mRNA show that it is restricted to dental mesenchyme during morphogenesis and that epithelial signals regulate Osf2/Cbfa1 expression in mandibular/dental mesenchyme. Cbfal(-/-)_ molar organs show aberrations in size and shape and fail to advance beyond the early bell stage. They lack overt odontoblast differentiation and normal dentin. These data suggest that Osf2/Cbfa! plays a non redundant role in tooth development. The proposed studies will test the central hypothesis that Osf2/Cbfa1 is a key mesenchymal factor with two critical functions in tooth development, one to influence the morphogenetic patterning of dental epithelium, and the other to establish the competence of dental mesenchyme to respond to epithelial signals that subsequently direct the differentiation of odontoblasts.
Aim 1 will analyze the expression of Osf2/Cbfa1 mrna and protein and will assess the histologic and molecular changes in Cbfa1(+/-) and Cbfal(-/-) dentition.
Aim 2 will study the developmental fate of Cbfa1(-/-) tooth organs when transplanted into wildtype mice and will use epithelial-mesenchymal recombination to assess when and where in tooth morphogenesis and cytodifferentiation, Osf2/Cbfa1 exerts its most critical influence.
In Aim 3, the involvement of Osf2/Cbfa1 with signaling molecules that influence tooth morphogenesis and cytodifferentiation will be studied.
Aim 4 will directly assess Osf2/Cbfa1's role in the differentiation and function of odontoblasts. DNA transfection and antisense oligonucleotide blocking assays will assess whether Osf2/Cbfa1 can induce/upregulate the expression of dentin ECM genes in established pre-odontoblastic and odontoblastic cell lines. Finally, dominant-negative transgenics that express a transcriptonally inactive form of Osf2/Cbfa1 driven by the osteocalcin promoter will be used to study the role of Osf2/Cbfa1 in maintaining the functional odontoblast phenotype. These data will establish Osf2/Cbfa1's role/s in tooth organogenesis and will provide new insights into the biology of tooth development that are critical to our understanding of the pathogenesis of genetic and acquired diseases that involve dentition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013368-03
Application #
6379954
Study Section
Special Emphasis Panel (ZRG1-GRM (03))
Program Officer
Small, Rochelle K
Project Start
1999-08-01
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
3
Fiscal Year
2001
Total Cost
$253,716
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Psychology
Type
Schools of Public Health
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Meng, Tian; Huang, Yanyu; Wang, Suzhen et al. (2015) Twist1 Is Essential for Tooth Morphogenesis and Odontoblast Differentiation. J Biol Chem 290:29593-602
Huang, Yanyu; Meng, Tian; Wang, Suzhen et al. (2014) Twist1- and Twist2-haploinsufficiency results in reduced bone formation. PLoS One 9:e99331
Siyam, Arwa; Wang, Suzhen; Qin, Chunlin et al. (2012) Nuclear localization of DMP1 proteins suggests a role in intracellular signaling. Biochem Biophys Res Commun 424:641-6
Lu, Yongbo; Li, Yucheng; Cavender, Adriana C et al. (2012) Molecular studies on the roles of Runx2 and Twist1 in regulating FGF signaling. Dev Dyn 241:1708-15
Li, Y; Lu, Y; Maciejewska, I et al. (2011) TWIST1 promotes the odontoblast-like differentiation of dental stem cells. Adv Dent Res 23:280-4
Galler, K M; Yasue, A; Cavender, A C et al. (2007) A novel role for Twist-1 in pulp homeostasis. J Dent Res 86:951-5
D'Souza, Rena N; Klein, Ophir D (2007) Unraveling the molecular mechanisms that lead to supernumerary teeth in mice and men: current concepts and novel approaches. Cells Tissues Organs 186:60-9
Bronckers, Antonius L J J; Sasaguri, Kenichi; Cavender, Adriana C et al. (2005) Expression of Runx2/Cbfa1/Pebp2alphaA during angiogenesis in postnatal rodent and fetal human orofacial tissues. J Bone Miner Res 20:428-37
Aberg, Thomas; Wang, Xiu-Ping; Kim, Jung-Hwan et al. (2004) Runx2 mediates FGF signaling from epithelium to mesenchyme during tooth morphogenesis. Dev Biol 270:76-93
Aberg, Thomas; Cavender, Adriana; Gaikwad, Joel S et al. (2004) Phenotypic changes in dentition of Runx2 homozygote-null mutant mice. J Histochem Cytochem 52:131-9

Showing the most recent 10 out of 16 publications