The role of Axin2 in calvarial morphogenesis and craniosynostosis
The role of Axin2 in calvarial morphogenesis and craniosynostosis
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DOI：
10.1242/dev.01786
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发表时间：
2005-04-01
期刊：
影响因子：
4.6
通讯作者：
Hsu, W
中科院分区：
文献类型：
--
作者：
Yu, HMI;Jerchow, B;Hsu, W
Axin 1及其同源物Axin 2/conductin/Axil是经典Wnt通路的负调节因子，其通过促进β-连环蛋白的降解来抑制信号转导。Axin 1缺失的小鼠在早期胚胎发育过程中表现出轴确定和脑模式的缺陷。我们发现Axin 2在颅骨形态发生过程中的成骨前缘和发育缝的骨膜中表达。在小鼠中靶向破坏Axin 2诱导颅骨结构畸形，这是一种类似于人类颅缝早闭症的表型。在突变体中，颅缝的过早融合发生在出生后早期。为了阐明颅缝早闭的机制，我们研究了Axin 2基因敲除小鼠的膜内骨化。Axin 2突变对颅骨成骨细胞发育有显著影响。Axin 2突变体显示骨祖细胞的扩增增强、骨化加速、成骨标志物的刺激表达和矿化增加。Axin 2的失活促进体内和体外成骨细胞增殖和分化。此外，由于哺乳动物的头骨是由来自中胚层和神经嵴的颅骨成骨间充质形成的，我们的数据表明Axin 2对神经嵴依赖性骨骼发生具有区域特异性作用。Axin 2突变引起的颅面畸形是通过激活β-连环蛋白信号传导介导的，这表明Wnt通路在颅骨形态发生中的新作用。
Axin1 and its homolog Axin2/conductin/Axil are negative regulators of the canonical Wnt pathway that suppress signal transduction by promoting degradation of beta-catenin. Mice with deletion of Axin1 exhibit defects in axis determination and brain patterning during early embryonic development. We show that Axin2 is expressed in the osteogenic fronts and periosteum of developing sutures during skull morphogenesis. Targeted disruption of Axin2 in mice induces malformations of skull structures, a phenotype resembling craniosynostosis in humans. In the mutants, premature fusion of cranial sutures occurs at early postnatal stages. To elucidate the mechanism of craniosynostosis, we studied intramembranous ossification in Axin2-null mice. The calvarial osteoblast development is significantly affected by the Axin2 mutation. The Axin2 mutant displays enhanced expansion of osteoprogenitors, accelerated ossification, stimulated expression of osteogenic markers and increases in mineralization. Inactivation of Axin2 promotes osteoblast proliferation and differentiation in vivo and in vitro. Furthermore, as the mammalian skull is formed from cranial skeletogenic mesenchyme, which is derived from mesoderm and neural crest, our data argue for a region-specific effect of Axin2 on neural crest dependent skeletogenesis. The craniofacial anomalies caused by the Axin2 mutation are mediated through activation of beta-catenin signaling, suggesting a novel role for the Wnt pathway in skull morphogenesis.