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 #
3R01DE013368-03S1
Application #
6474949
Study Section
Special Emphasis Panel (ZRG1 (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
$158,409
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
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