title: Molecular studies on the roles of Runx2 and Twist1 in regulating FGF signaling.
abstract: BACKGROUND
  Supernumerary teeth are often observed in patients suffering from cleidocranial dysplasia due to a mutation in Runx2 that results in haploinsufficiency. However, the underlying molecular mechanisms are poorly defined. In this study, we assessed the roles of Runx2 and its functional antagonist Twist1 in regulating fibroblast growth factor (FGF) signaling using in vitro biochemical approaches.
  
  
  RESULTS
  We showed that Twist1 stimulated Fgfr2 and Fgf10 expression in a mesenchymal cell line and that it formed heterodimers with ubiquitously expressed E12 (together with E47 encoded by E2A gene) and upregulated Fgfr2 and Fgf10 promoter activities in a dental mesenchyme-derived cell line. We further demonstrated that the bHLH domain of Twist1 was essential for its synergistic activation of Fgfr2 promoter with E12 and that the binding of E12 stabilized Twist1 by preventing it from undergoing lysosomal degradation. Although Runx2 had no apparent effects on Fgfr2 and Fgf10 promoter activities, it inhibited the stimulatory activity of Twist1 on Fgfr2 promoter.
  
  
  CONCLUSIONS
  These findings suggest that Runx2 haploinsufficiency might result in excessive unbound Twist1 that can freely bind to E12 and enhance FGF signaling, thereby promoting the formation of extra teeth.
authors.affiliation: Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, TX 75246, USA.
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Lu
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Li
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Cavender
authors.forename: Suzhen
authors.initials: S
authors.lastname: Wang
authors.forename: Alka
authors.initials: A
authors.lastname: Mansukhani
authors.forename: Rena N
authors.initials: RN
authors.lastname: D'Souza
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D009687:Nuclear Proteins; C493716:Runx2 protein, mouse; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse; D005346:Fibroblast Growth Factors; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2