The underlying hypothesis for the proposed studies is that bone morphogenetic protein 4 (Bmp4) is a key component in the tooth formation process, and the cis-DNA domains of Bmp4 gene control the spatial and temporal expression of Bmp4 during development. We have previously dissected out control domains for Bmp4 expression in ameloblasts by the transgenic approach. We have also generated transgenic mice to study Bmp4 function, in which a human Bmp4 cDNA is driven by this 1.1 kb mouse Bmp4 promoter. These Bmp4 transgenic mice display profound tooth abnormalities.
In AIM 1, we will determine the role of Bmp4 in enamel morphogenesis and mineralization by characterizing the enamel phenotype of human Bmp4 transgenic mice. Finishing this aim we should be able to provide evidence to support our hypothesis that Bmp4 plays an active role in preventing cell and tissue over proliferation/differentiation by virtue of its effects on apoptosis during development.
In AIM 2, we plan to generate transgenic mice expressing lacZ reporter construct driven by the 5' and 3' flanking regions of the Bmp4 gene as well as the introns. We will then compare the expression patterns of the reporter transgene to those in Bmp4 lacZ knock-in mice where the lacZ reporter gene is under control of the entire Bmp4 promoter. Finishing this aim we should be able to identify most if not all control domains that control Bmp4 expression in ameloblasts, cementoblasts, odontoblasts, osteoblasts, and osteocytes, as well as enamel knot and other primordial tooth cells. Successful conclusion of this research, with Bmp4 lacZ knock-in mouse (a gift from Dr. Bridge Hogan) and human Bmp4 mouse models already established, will have high probability of providing important information in understanding the tooth formation process.
