Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation.
Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation.
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DOI：
10.1083/jcb.200409182
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发表时间：
2005-03-28
期刊：
影响因子：
--
通讯作者：
Basilico C
中科院分区：
文献类型：
--
作者：
Mansukhani A;Ambrosetti D;Holmes G;Cornivelli L;Basilico C
成纤维细胞生长因子受体2(FGFR2)的激活突变通过影响形成颅骨的成骨细胞的增殖和分化而导致几种颅缝融合综合征。成骨细胞对成纤维细胞生长有促进作用，对分化有抑制作用。我们分析了表达FGFR2激活突变(C342Y或S252W)的成骨细胞的基因表达谱，发现许多Wnt靶基因的表达显著下调，并伴随着转录因子Sox2的诱导。用外源性成纤维细胞生长因子处理成骨细胞可以复制这些变化。WNT信号促进成骨细胞功能，调节骨量。Sox2在活体颅骨成骨细胞中表达，我们发现Sox2的结构性表达抑制了成骨细胞的分化，并导致许多Wnt靶基因的表达下调。SOX2与成骨细胞中的β-连环蛋白结合，并通过其COOH端结构域抑制WNT反应性报告质粒的活性。我们的结果表明，成纤维细胞生长因子信号可以通过诱导SOX2和调节Wnt-β-Catenin通路来调控成骨细胞分化的多个方面。
Activating mutations in fibroblast growth factor receptor 2 (FGFR2) cause several craniosynostosis syndromes by affecting the proliferation and differentiation of osteoblasts, which form the calvarial bones. Osteoblasts respond to FGF with increased proliferation and inhibition of differentiation. We analyzed the gene expression profiles of osteoblasts expressing FGFR2 activating mutations (C342Y or S252W) and found a striking down-regulation of the expression of many Wnt target genes and a concomitant induction of the transcription factor Sox2. Most of these changes could be reproduced by treatment of osteoblasts with exogenous FGF. Wnt signals promote osteoblast function and regulate bone mass. Sox2 is expressed in calvarial osteoblasts in vivo and we show that constitutive expression of Sox2 inhibits osteoblast differentiation and causes down-regulation of the expression of numerous Wnt target genes. Sox2 associates with β-catenin in osteoblasts and can inhibit the activity of a Wnt responsive reporter plasmid through its COOH-terminal domain. Our results indicate that FGF signaling could control many aspects of osteoblast differentiation through induction of Sox2 and regulation of the Wnt–β-catenin pathway.
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