Early onset of craniosynostosis in an Apert mouse model reveals critical features of this pathology.
Early onset of craniosynostosis in an Apert mouse model reveals critical features of this pathology.
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DOI：
10.1016/j.ydbio.2009.01.026
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发表时间：
2009-04-15
影响因子：
2.7
通讯作者：
Basilico, Claudio
中科院分区：
文献类型：
--
作者：
Holmes, Greg;Rothschild, Gerson;Roy, Upal Basu;Deng, Chu-Xia;Mansukhani, Alka;Basilico, Claudio
关键词：
FGFRs 1 -3的激活突变导致人和小鼠的颅缝早闭（CS），即颅骨的过早融合。这种突变导致CS的机制被不同地归因于成骨细胞增殖、分化和凋亡的增加，但这些干扰如何与缝线融合的过程相关并不总是清楚的。我们在Apert Fgfr 2（S252 W）小鼠模型中重新评估了冠状缝融合。我们发现，CS的关键事件是早期损失的基础缝间充质的成骨前线，表达活化Fgfr 2，团结形成一个连续的成骨膜。骨祖细胞增殖的轻度增加先于但不伴随该事件，并且细胞凋亡是不显著的。另一方面，更顶端的冠状缝最初适当地形成，但随后经历融合，尽管速度较慢，伴随着骨祖细胞增殖的显著减少和成骨细胞成熟的增加。细胞凋亡现在伴随着融合，但仅限于彼此接触的骨前缘。我们将这些体内观察结果与培养中的原代成骨细胞中激活的Fgfr 2 S252 W突变的内在效应相关联，其显示出增殖和分化的能力增加。我们的研究表明，Fgfr 2诱导的颅缝早闭的主要决定因素是对信号的反应失败，这些信号将停止骨祖细胞在缝线正常形成的部位的募集或推进。
Activating mutations of FGFRs1–3 cause craniosynostosis (CS), the premature fusion of cranial bones, in man and mouse. The mechanisms by which such mutations lead to CS have been variously ascribed to increased osteoblast proliferation, differentiation, and apoptosis, but it is not always clear how these disturbances relate to the process of suture fusion. We have reassessed coronal suture fusion in an Apert Fgfr2 (S252W) mouse model. We find that the critical event of CS is the early loss of basal sutural mesenchyme as the osteogenic fronts, expressing activated Fgfr2, unite to form a contiguous skeletogenic membrane. A mild increase in osteoprogenitor proliferation precedes but does not accompany this event, and apoptosis is insignificant. On the other hand, the more apical coronal suture initially forms appropriately but then undergoes fusion, albeit at a slower rate, accompanied by a significant decrease in osteoprogenitor proliferation, and increased osteoblast maturation. Apoptosis now accompanies fusion, but is restricted to bone fronts in contact with one another. We correlated these in vivo observations with the intrinsic effects of the activated Fgfr2 S252W mutation in primary osteoblasts in culture, which show an increased capacity for both proliferation and differentiation. Our studies suggest that the major determinant of Fgfr2-induced craniosynostosis is the failure to respond to signals that would halt the recruitment or the advancement of osteoprogenitor cells at the sites where sutures should normally form.
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影响因子：
2.7
作者：
Holmbeck, K
通讯作者：
Holmbeck, K
影响因子：
--
作者：
Carver, EA;Oram, KF;Gridley, T
通讯作者：
Gridley, T
影响因子：
11.8
作者：
Bialek, P;Kern, B;Karsenty, G
通讯作者：
Karsenty, G
DOI：
10.1073/pnas.071586898
发表时间：
2001-03-27
影响因子：
11.1
作者：
Hajihosseini, MK;Wilson, S;Dickson, C
通讯作者：
Dickson, C
影响因子：
4.8
作者：
Hu, YY;Chan, E;Li, BJ
通讯作者：
Li, BJ