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 feedback 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.

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE018885-01A2
Application #
7731580
Study Section
Special Emphasis Panel (ZRG1-MOSS-K (09))
Program Officer
Scholnick, Steven
Project Start
2009-07-01
Project End
2013-03-31
Budget Start
2009-07-01
Budget End
2010-03-31
Support Year
1
Fiscal Year
2009
Total Cost
$366,250
Indirect Cost
Name
Texas A&M University
Department
Genetics
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
Yu, Wenjie; Li, Xiao; Eliason, Steven et al. (2017) Irx1 regulates dental outer enamel epithelial and lung alveolar type II epithelial differentiation. Dev Biol 429:44-55
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
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
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
Li, Xiao; Florez, Sergio; Wang, Jianbo et al. (2013) Dact2 represses PITX2 transcriptional activation and cell proliferation through Wnt/beta-catenin signaling during odontogenesis. PLoS One 8:e54868
Zhang, Zichao; Gutierrez, Diana; Li, Xiao et al. (2013) The LIM homeodomain transcription factor LHX6: a transcriptional repressor that interacts with pituitary homeobox 2 (PITX2) to regulate odontogenesis. J Biol Chem 288:2485-500
Zhang, Zichao; Wlodarczyk, Bogdan J; Niederreither, Karen et al. (2011) Fuz regulates craniofacial development through tissue specific responses to signaling factors. PLoS One 6:e24608
Cao, H; Wang, J; Li, X et al. (2010) MicroRNAs play a critical role in tooth development. J Dent Res 89:779-84
Cao, Huojun; Florez, Sergio; Amen, Melanie et al. (2010) Tbx1 regulates progenitor cell proliferation in the dental epithelium by modulating Pitx2 activation of p21. Dev Biol 347:289-300