Human Molecular Genetics Advance Access originally published online on August 22, 2008
Human Molecular Genetics 2008 17(23):3643-3654; doi:10.1093/hmg/ddn258
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Novel expression and transcriptional regulation of FoxJ1 during oro-facial morphogenesis
1 Texas A&M Health Science Center, Institute of Biosciences and Technology, Houston, TX, USA 2 Texas A&M Health Science Center, Baylor College of Dentistry, Dallas, TX, USA 3 Department of Experimental Medical Research, Lund University, Lund, Sweden 4 Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA
* To whom correspondence should be addressed at: TAMU Health Science Center, Institute of Biosciences and Technology, 2121 West Holcombe Boulevard, Houston, TX 77030, USA. Tel: +1 7136777402; Fax: +1 7136777784; Email: bamendt{at}ibt.tamhsc.edu
Received May 28, 2008; Accepted August 20, 2008
Axenfeld–Rieger syndrome (ARS) patients with PITX2 point mutations exhibit a wide range of clinical features including mild craniofacial dysmorphism and dental anomalies. Identifying new PITX2 targets and transcriptional mechanisms are important to understand the molecular basis of these anomalies. Chromatin immunoprecipitation assays demonstrate PITX2 binding to the FoxJ1 promoter and PITX2C transgenic mouse fibroblasts and PITX2-transfected cells have increased endogenous FoxJ1 expression. FoxJ1 is expressed at embryonic day 14.5 (E14.5) in early tooth germs, then down-regulated from E15.5–E17.5 and re-expressed in the inner enamel epithelium, oral epithelium, tongue epithelium, sub-mandibular salivary gland and hair follicles during E18.5 and neonate day 1. FoxJ1 and Pitx2 exhibit overlapping expression patterns in the dental and oral epithelium. PITX2 activates the FoxJ1 promoter and, Lef-1 and β-catenin interact with PITX2 to synergistically regulate the FoxJ1 promoter. FoxJ1 physically interacts with the PITX2 homeodomain to synergistically regulate FoxJ1, providing a positive feedback mechanism for FoxJ1 expression. Furthermore, FoxJ1, PITX2, Lef-1 and β-catenin act in concert to activate the FoxJ1 promoter. The PITX2 T68P ARS mutant protein physically interacts with FoxJ1; however, it cannot activate the FoxJ1 promoter. These data indicate a mechanism for the activity of the ARS mutant proteins in specific cell types and provides a basis for craniofacial/ tooth anomalies observed in these patients. These data reveal novel transcriptional mechanisms of FoxJ1 and demonstrate a new role of FoxJ1 in oro-facial morphogenesis.