Direct interactions of Runx2 and canonical Wnt signaling induce FGF18
Direct interactions of Runx2 and canonical Wnt signaling induce FGF18
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DOI：
10.1074/jbc.m608995200
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发表时间：
2007-02-09
影响因子：
4.8
通讯作者：
Naski, Michael C.
中科院分区：
文献类型：
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作者：
Reinhold, Martina I.;Naski, Michael C.
典型的Wnt信号传导显然是骨骼发育和骨形成所必需的。然而，Wnt信号转导的靶点将该信号转化为骨尚不清楚。这些目标的鉴定将产生对正常骨生理学的了解，并提出治疗骨病的新疗法。在这里，我们表明，一个重要的调节骨发育，FGF 18，是一个直接目标的经典Writ信号。Wnt依赖性转录因子TCF/Lef的单个DNA结合位点解释了fgf 18启动子响应Wnt信号的刺激。此外，靶向破坏β cat阻断了体内fgf 18表达。与TCF/Lef结合位点部分重叠的是Runx 2结合位点，实验表明Runx 2和TCF/Lef协同作用以诱导fgf 18表达。RNA干扰敲低Runx 2抑制和Runx 2强制表达增强了经典Writ信号转导对fgf 18的诱导。值得注意的是，Runx 2与Lef 1或TCF 4形成复合物，并且该复合物结合fgf 18启动子中的复合结合位点。这些结果表明，两个转录途径是必不可少的骨，物理和功能上的fgf 18启动子收敛。
Canonical Wnt signaling is clearly required for skeletal development and bone formation. However, the targets of Wnt signaling that convert this signal into bone are unclear. Identification of these targets will yield insight into normal bone physiology and suggest new therapeutics for treatment of bone disease. Here we show that an essential regulator of bone development, FGF18, is a direct target of canonical Writ signaling. A single DNA binding site for the Wnt-dependent transcription factors TCF/Lef accounted for the stimulation of fgf18 promoter in response to Wnt signaling. Additionally, targeted disruption of beta cat blocked fgf18 expression in vivo. Partially overlapping the TCF/Lef binding site is a Runx2 binding site and experiments showed that Runx2 and TCF/Lef work cooperatively to induced fgf18 expression. RNA interference knockdown of Runx2 inhibited and Runx2 forced expression augmented the induction of fgf18 by canonical Writ signaling. Significantly, Runx2 formed a complex with Lef1 or TCF4 and this complex bound the composite binding site in the fgf18 promoter. These results demonstrate that two transcription pathways that are essential for bone, physically and functionally converge at the fgf18 promoter.