Snail1 is a transcriptional effector of FGFR3 signaling during chondrogenesis and achondroplasias
Snail1 is a transcriptional effector of FGFR3 signaling during chondrogenesis and achondroplasias
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DOI：
10.1016/j.devcel.2007.09.016
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发表时间：
2007-12-01
影响因子：
11.8
通讯作者：
Nieto, M. Angela
中科院分区：
文献类型：
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作者：
de Frutos, Cristina A.;Vega, Sonia;Nieto, M. Angela
软骨发育不全是人类侏儒症最常见的遗传形式。它们与FGFR3中的激活突变相关，FGFR3以配体非依赖性方式通过Stat和MAPK途径发出信号，以损害软骨细胞增殖和分化。Snail 1与软骨细胞分化有关，因为它在体外抑制胶原II和聚集蛋白聚糖的转录。在这里，我们证明了Snail1在发育中的骨骼过度表达导致小鼠软骨发育不全。Snail1在软骨细胞中作用于FGFR3信号传导的下游，调节Stat和MAPK通路。此外，FGFR3在骨发育和疾病期间需要Snail 1，因为Snail 1的抑制甚至通过软骨发育不全和致死性激活FGFR3形式消除其信号传导。值得注意的是，蜗牛1是异常上调，在thanatophoric与正常软骨从stillaries。因此，Snail活性可能被认为是软骨发育不全治疗的靶点。
Achondroplasias are the most common genetic forms of dwarfism in humans. They are associated with activating mutations in FGFR3, which signal through the Stat and MAPK pathways in a ligand-independent manner to impair chondrocyte proliferation and differentiation. Snail1 has been implicated in chondrocyte differentiation as it represses Collagen II and aggrecan transcription in vitro. Here we demonstrate that Snail1 overexpression in the developing bone leads to achondroplasia in mice. Snail1 acts downstream of FGFR3 signaling in chondrocytes, regulating both Stat and MAPK pathways. Moreover, FGFR3 requires Snail1 during bone development and disease as the inhibition of Snail1 abolishes its signaling even through achondroplastic- and thanatophoric-activating FGFR3 forms. Significantly, Snail1 is aberrantly upregulated in thanatophoric versus normal cartilages from stillborns. Thus, Snail activity may likely be considered a target for achondroplasia therapies.