A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures
A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures
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DOI：
10.1093/hmg/9.13.2001
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发表时间：
2000-08-12
影响因子：
3.5
通讯作者：
Deng, CX
中科院分区：
文献类型：
--
作者：
Zhou, YX;Xu, XL;Deng, CX
Pfeiffer综合征是颅缝早闭的一种典型形式，其由成纤维细胞生长因子受体1（FGFR 1）中氨基酸252（Pro252 Arg）处的脯氨酸->精氨酸取代引起。在这里，我们发现携带Fgfr 1中的Pro250 Arg突变的小鼠，其与人类中的Pfeiffer综合征突变是正交的，表现出前后缩短、侧向加宽和垂直升高的神经颅。对出生后早期突变小鼠的后额叶和前额叶、矢状和冠状缝的分析显示过早融合，突变小鼠的骨缝加速了成骨细胞增殖，并增加了与成骨细胞分化相关的基因表达，这表明在Pfeiffer综合征中，骨缝处的骨形成局部增加。值得注意的是，核心结合转录因子a亚基1（Cbfa 1）的表达显著增加伴随过早融合，表明Cbfa 1可能是Fgf/Fgfr 1信号的下游靶点。这在体外得到了证实，我们证明了野生型或突变型Fgfr 1转染诱导Cbfa 1表达。这些研究提供了FGFR 1中Pro252 Arg突变导致人类Pfeiffer综合征的直接遗传学证据，并揭示了Fgf/Fgfr 1信号通过调节Cbfa 1表达来调节膜内骨形成的分子机制。
Pfeiffer syndrome is a classic form of craniosynostosis that is caused by a proline-->arginine substitution at amino acid 252 (Pro252Arg) in fibroblast growth factor receptor 1 (FGFR1). Here we show that mice carrying a Pro250Arg mutation in Fgfr1, which is orthologous to the Pfeiffer syndrome mutation in humans, exhibit anterio-posteriorly shortened, laterally widened and vertically heightened neurocraniums, Analysis of the posterior and anterior frontal, sagittal and coronal sutures of early post-natal mutant mice revealed premature fusion, The sutures of mutant mice had accelerated osteoblast proliferation and increased expression of genes related to osteoblast differentiation, suggesting that bone formation at the sutures is locally increased in Pfeiffer syndrome. Of note, dramatically increased expression of core-binding transcription factor a subunit type 1 (Cbfa1) accompanied premature fusion, suggesting that Cbfa1 may be a downstream target of Fgf/Fgfr1 signals. This was confirmed in vitro, where we demonstrate that transfection with wild-type or mutant Fgfr1 induces Cbfa1 expression. The induced expression was also observed using Fgf ligands (Fgf2 and Fgf8), These studies provide direct genetic evidence that the Pro252Arg mutation in FGFR1 causes human Pfeiffer syndrome and uncovers a molecular mechanism in which Fgf/Fgfr1 signals regulate intramembraneous bone formation by modulating Cbfa1 expression.