Mechanisms of FoxJ1 in tooth morphogenesis

University Of Iowa, Iowa City IA

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Abstract

Principal Investigator/Program Director (Last, First, Middle): DESCRIPTION: See instructions. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. In recent years a number of new genes have been identified that are involved in tooth morphogenesis. Though much progress has been made in identifying new genes and the signaling mechanisms that regulate morphogenetic stages of tooth development have been documented, the transcriptional mechanisms that regulate cytodifferentiation of the odontoblasts and ameloblasts are poorly understood. Better understanding of the mechanistic aspect of this process is necessary, not only to understand normal tooth morphogenesis, but also to regenerate teeth, and eventually be able to develop and deliver better therapeutic strategies. Our lab has identified FoxJ1 as a new transcription factor involved in late stage tooth and craniofacial morphogenesis. FoxJ1 (also known as HFH-4, FHKL-13) belongs to the fork-head family of genes, containing a fork-head (also known as winged helix) DNA binding domain is known to regulate development via cell fate determination. Our preliminary data reveals FoxJ1 expression in the mouse molar inner dental epithelium from E18.5 onwards and in the pre-ameloblasts and odontoblasts during neonate day 1. It is also expressed in the oral epithelium and sub-mandibular salivary gland during E17.5 and neonate day 1. Our transient transfection data indicates that FoxJ1 is activated by, and also physically interacts with PITX2, a homeobox transcription factor gene involved in early craniofacial/tooth development. The overall goal of this proposal is to test our hypothesis that FoxJ1 plays a role in cytodifferentiation of ameloblasts and odontoblasts during tooth development using mouse genetics. We will test our hypothesis that PITX2 regulates FoxJ1 expression in concert with other transcription factors during tooth development. Moreover, FoxJ1 physically interacts with PITX2 and auto-regulates its promoter in a positive feed back fashion. We will test our hypothesis that FoxJ1 interacts with PITX2 and other tooth specific transcription factors to regulate late bell and pre-secretory stages of tooth development.The identification of new genes involved in craniofacial/tooth development will increase our knowledge about the basic development programs required for normal embryogenesis. Understanding how these components interact to promote normal craniofacial development will further our understanding of genetic defects. We can then promote methodologies to inhibit severe craniofacial anomalies. PERFORMANCE SITE(S) (organization, city, state) Texas A&M Health Science Center, Institute for Biosciences and Technology, Houston, TX PHS 398 (Rev. 04/06) Page 2 Form Page 2