Molecular studies on the roles of Runx2 and Twist1 in regulating FGF signaling
Article first published online: 17 SEP 2012
Copyright © 2012 Wiley Periodicals, Inc.
Volume 241, Issue 11, pages 1708–1715, November 2012
How to Cite
Lu, Y., Li, Y., Cavender, A. C., Wang, S., Mansukhani, A. and D'Souza, R. N. (2012), Molecular studies on the roles of Runx2 and Twist1 in regulating FGF signaling. Dev. Dyn., 241: 1708–1715. doi: 10.1002/dvdy.23858
- Issue published online: 17 OCT 2012
- Article first published online: 17 SEP 2012
- Accepted manuscript online: 12 SEP 2012 02:26PM EST
- Manuscript Accepted: 16 AUG 2012
- NIDCR/NIH. Grant Numbers: DE013368, DE16472, DE021773
- tooth morphogenesis
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. Developmental Dynamics 241:1708–1715, 2012. © 2012 Wiley Periodicals, Inc.