Bmp signaling has a central role in craniofacial and tooth development. However, firm understanding about the role of Bmp signaling in craniofacial morphogenesis has been limited by the early embryonic lethality of the Bmp4 and Bmp2 null mutant mice. Bmp signaling has been implicated in fundamentally important events such as tooth-type morphogenesis, tooth organ placement, and in the effector pathways that are critical for the final morphogenetic events in tooth development. This research program will directly investigate the function of Bmp4 in tooth morphogenesis by generating a Bmp4 conditional null allele by gene targeting in embryonic stem cells. We propose to dissect the temporal requirements for Bmp4 signaling in tooth morphogenesis by using different cre recombinase transgenic mice that drive cre recombinase activity at distinct time points. Moreover, we will use a transgenic line that utilizes a fusion between cre recombinase and a mutant form of the estrogen receptor to temporally control inactivation of Bmp4 in dental epithelium. We will address the hypothesis that proximo-distal patterning of the first branchial arch is mediated by a Bmp4 activity gradient by generating a Bmp4 GFP fusion allele to directly visualize the Bmp4 ligand spread in vivo. We will investigate the kinetics of Bmp4 ligand spread in oral and dental epithelium by generating a Bmp4GFP allele that is regulated by tetracycline. This research program will provide new insight into the function and regulation of Bmp4 in tooth development.
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