Gene disruption of Spred-2 causes dwarfism
Gene disruption of Spred-2 causes dwarfism
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DOI：
10.1074/jbc.m503640200
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发表时间：
2005-08-05
影响因子：
4.8
通讯作者：
Schuh, K
中科院分区：
文献类型：
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作者：
Bundschu, K;Knobeloch, KP;Schuh, K
成纤维细胞生长因子受体3（FGFR 3）介导的信号通路对骨生长的影响已通过各种遗传学方法得到证实。成纤维细胞生长因子（FGF）的过表达、FGFR 3中的几种功能获得性突变以及软骨细胞中丝裂原活化蛋白激酶（MAPK）激酶（MEK 1）的组成性激活已被证明通过激活MAPK信号通路导致小鼠侏儒症。为了研究先前报道的Spred在FGFR 3/MAPK通路中的抑制作用，我们产生了具有捕获的Spred-2基因的小鼠。在这里，我们表明，缺乏功能性的Spred-2蛋白在小鼠引起侏儒表型，类似软骨发育不全，最常见的人类侏儒症的形式。与野生型小鼠相比，Spred-2（-/-）小鼠表现出生长和体重降低，胫骨长度缩短，生长板变窄。我们检测了Spred-2在软骨细胞中的启动子活性和蛋白表达，表明Spred- 2在软骨细胞和骨发育中的重要功能。与Spred-2（+/+）软骨细胞相比，用不同FGF浓度刺激软骨细胞显示在Spred-2（-/-）软骨细胞中ERK磷酸化更早且增强。我们的观察结果表明，在一个模型中，损失的Spred- 2抑制骨生长的抑制软骨细胞分化通过上调MAPK信号通路。
The impact of the fibroblast growth factor receptor 3 ( FGFR3)-mediated signaling pathway on bone growth has been demonstrated by various genetic approaches. Overexpression of fibroblast growth factors ( FGFs), several gain-of-function mutations in the FGFR3, and constitutive activation of mitogen-activated protein kinase ( MAPK) kinase ( MEK1) in chondrocytes have been shown to cause dwarfism in mice by activation of the MAPK signaling pathway. To investigate the previously reported inhibitory role of Spred in the FGFR3/MAPK pathway, we generated mice with a trapped Spred-2 gene. Here we show that lack of functional Spred-2 protein in mice caused a dwarf phenotype, similar to achondroplasia, the most common form of human dwarfism. Spred-2(-/-) mice showed reduced growth and body weight, they had a shorter tibia length, and showed narrower growth plates as compared with wild-type mice. We detected promoter activity and protein expression of Spred-2 in chondrocytes, suggesting an important function of Spred- 2 in chondrocytes and bone development. Stimulation of chondrocytes with different FGF concentrations showed earlier and augmented ERK phosphorylation in Spred-2(-/-) chondrocytes in comparison to Spred-2(+/+) chondrocytes. Our observations suggest a model in which loss of Spred- 2 inhibits bone growth by inhibiting chondrocyte differentiation through up-regulation of the MAPK signaling pathway.