Molecular studies on the roles of Runx2 and Twist1 in regulating FGF signaling

被引:21
作者
Lu, Yongbo [1 ]
Li, Yucheng [1 ,2 ]
Cavender, Adriana C. [1 ]
Wang, Suzhen [1 ]
Mansukhani, Alka [3 ]
D'Souza, Rena N. [1 ]
机构
[1] Baylor Coll Dent, Dept Biomed Sci, Texas A&M Hlth Sci Ctr, Dallas, TX 75246 USA
[2] Fourth Mil Med Univ, Dept Operat Dent & Endodont, Sch Stomatol, Xian 710032, Shaanxi, Peoples R China
[3] NYU, Med Ctr, Langone Med Ctr, New York, NY 10016 USA
关键词
Runx2; Twist1; E12; FGF10; Fgfr2; tooth morphogenesis; SAETHRE-CHOTZEN-SYNDROME; CLEIDOCRANIAL DYSPLASIA; OSTEOBLAST DIFFERENTIATION; TOOTH MORPHOGENESIS; BONE-DEVELOPMENT; DNA-BINDING; MUTATIONS; SPROUTY; CBFA1; EXPRESSION;
D O I
10.1002/dvdy.23858
中图分类号
R602 [外科病理学、解剖学]; R32 [人体形态学];
学科分类号
100101 ;
摘要
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 241:17081715, 2012. (c) 2012 Wiley Periodicals, Inc.
引用
收藏
页码:1708 / 1715
页数:8
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