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 proliferation and differentiation 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. PITX2 provides a unique tool for studying the molecular control of tooth formation since it is selectively expressed at the earliest stage of tooth development. We have only begun to understand the molecular mechanisms of PITX2, its role in tooth development and the downstream hierarchy of transcription factors involved in craniofacial/tooth development. The focus of this continuing grant application is to understand the molecular mechanisms by which PITX2 interacts with other factors to regulate tooth development. Our previous results demonstrate that PITX2 acts in concert with other factors to regulate gene expression. We propose to test our hypothesis that PITX2 differentially regulates gene expression through specific protein-protein interactions with T-box factors Tbx1 and Tbx18 and the LIM homeodomain factors Islet-1 and Lhx6. HMG-17, a chromatin associated factor recruits PITX2 to active chromatin and is activated through Wnt/-catenin signaling. We will test our hypothesis that the transcriptional activity of PITX2 is tightly regulated during development by its interaction with HMG-17, -catenin, acetylated histones and chromatin remodeling factors. MicroRNAs (miR's) are critical to controlling gene expression however little is known about their role in craniofacial/tooth development. Preliminary data demonstrates that miR's directly control the patterning of incisors and molars, specifying a combinatorial code of miR expression for normal craniofacial/tooth development. We will test our hypothesis that specific miR's expressed during tooth development control the activities of specific transcription factors and the patterning of teeth. Understanding how these components interact to promote normal craniofacial development will further our understanding of genetic defects.

Public Health Relevance

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 once a molecular basis has been assigned to a specific defect or component.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-K (09))
Program Officer
Scholnick, Steven
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University of Iowa
Anatomy/Cell Biology
Schools of Medicine
Iowa City
United States
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Sun, Zhao; Yu, Wenjie; Sanz Navarro, Maria et al. (2016) Sox2 and Lef-1 interact with Pitx2 to regulate incisor development and stem cell renewal. Development 143:4115-4126
Tao, Ge; Kahr, Peter C; Morikawa, Yuka et al. (2016) Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury. Nature 534:119-23
Cao, H; Yu, W; Li, X et al. (2016) A new plasmid-based microRNA inhibitor system that inhibits microRNA families in transgenic mice and cells: a potential new therapeutic reagent. Gene Ther 23:527-42
Gao, Shan; Moreno, Myriam; Eliason, Steven et al. (2015) TBX1 protein interactions and microRNA-96-5p regulation controls cell proliferation during craniofacial and dental development: implications for 22q11.2 deletion syndrome. Hum Mol Genet 24:2330-48
Zhang, Zichao; Kim, KyoungHyun; Li, Xiao et al. (2014) MicroRNA-26b represses colon cancer cell proliferation by inhibiting lymphoid enhancer factor 1 expression. Mol Cancer Ther 13:1942-51
Sharp, Thad; Wang, Jianbo; Li, Xiao et al. (2014) A pituitary homeobox 2 (Pitx2):microRNA-200a-3p:β-catenin pathway converts mesenchymal cells to amelogenin-expressing dental epithelial cells. J Biol Chem 289:27327-41
Gay, I; Cavender, A; Peto, D et al. (2014) Differentiation of human dental stem cells reveals a role for microRNA-218. J Periodontal Res 49:110-20
Li, Xiao; Venugopalan, Shankar R; Cao, Huojun et al. (2014) A model for the molecular underpinnings of tooth defects in Axenfeld-Rieger syndrome. Hum Mol Genet 23:194-208
Cao, Huojun; Jheon, Andrew; Li, Xiao et al. (2013) The Pitx2:miR-200c/141:noggin pathway regulates Bmp signaling and ameloblast differentiation. Development 140:3348-59
Gao, Shan; Li, Xiao; Amendt, Brad A (2013) Understanding the role of Tbx1 as a candidate gene for 22q11.2 deletion syndrome. Curr Allergy Asthma Rep 13:613-21

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