Activation of p38 MAPK pathway in the skull abnormalities of Apert syndrome Fgfr2(+P253R) mice.
Activation of p38 MAPK pathway in the skull abnormalities of Apert syndrome Fgfr2(+P253R) mice.
复制标题
DOI：
10.1186/1471-213x-10-22
复制
发表时间：
2010-02-22
影响因子：
--
通讯作者：
Jabs EW
中科院分区：
文献类型：
--
作者：
Wang Y;Sun M;Uhlhorn VL;Zhou X;Peter I;Martinez-Abadias N;Hill CA;Percival CJ;Richtsmeier JT;Huso DL;Jabs EW
Apert综合征以颅缝早闭和肢体畸形为特征，主要由FGFR 2 +/P253 R和+/S252 W突变引起。前一种突变存在于大约三分之一的患者中，而后一种突变存在于三分之二的患者中。我们先前报道了一种在C57 BL/6 J背景下具有Fgfr 2 +/S252 W突变的Apert综合征近交系转基因小鼠模型。在这里，我们提出了Fgfr 2 +/P253 R突变的小鼠模型。我们在相同的C56 BL/6 J遗传背景上产生近交Fgfr 2 +/P253 R小鼠，并分析它们的骨骼异常。Fgfr 2 +/P253 R小鼠颅骨的3D micro-CT扫描显示，在P0时，颅骨长度缩短，前颅底长度显著短于Fgfr 2 +/S252 W小鼠。Fgfr 2 +/P253 R小鼠表现为冠状缝和近侧前缘的骨性结合，矢状缝和齿状缝中的细胞结构紊乱。与Fgfr 2 +/S252 W小鼠一样，在Fgfr 2 +/P253 R小鼠的发育冠状缝和长骨处观察到异常的骨生成和增殖。Fgfr 2 +/P253 R脑颅中存在丝裂原活化蛋白激酶（MAPK）的激活，磷酸化p38和ERK 1/2表达增加，而磷酸化AKT和PKCα表达无明显变化。在不同突变的个体胚胎之间和相同突变的个体胚胎之间存在局部的表型和分子变异。我们的体内研究表明，Fgfr 2 +/P253 R突变导致小鼠的颅骨特征与Fgfr 2 +/S252 W小鼠和人类Apert综合征相似。除了ERK 1/2信号通路外，激活的p38可能介导突变的神经颅表型。虽然Apert综合征传统上被认为是一个一致的表型，我们的研究结果表明，局部和区域的特点Apert综合征的表型的变化。
Apert syndrome is characterized by craniosynostosis and limb abnormalities and is primarily caused by FGFR2 +/P253R and +/S252W mutations. The former mutation is present in approximately one third whereas the latter mutation is present in two-thirds of the patients with this condition. We previously reported an inbred transgenic mouse model with the Fgfr2 +/S252W mutation on the C57BL/6J background for Apert syndrome. Here we present a mouse model for the Fgfr2+/P253R mutation. We generated inbred Fgfr2+/P253R mice on the same C56BL/6J genetic background and analyzed their skeletal abnormalities. 3D micro-CT scans of the skulls of the Fgfr2+/P253R mice revealed that the skull length was shortened with the length of the anterior cranial base significantly shorter than that of the Fgfr2+/S252W mice at P0. The Fgfr2+/P253R mice presented with synostosis of the coronal suture and proximate fronts with disorganized cellularity in sagittal and lambdoid sutures. Abnormal osteogenesis and proliferation were observed at the developing coronal suture and long bones of the Fgfr2+/P253R mice as in the Fgfr2+/S252W mice. Activation of mitogen-activated protein kinases (MAPK) was observed in the Fgfr2+/P253R neurocranium with an increase in phosphorylated p38 as well as ERK1/2, whereas phosphorylated AKT and PKCα were not obviously changed as compared to those of wild-type controls. There were localized phenotypic and molecular variations among individual embryos with different mutations and among those with the same mutation. Our in vivo studies demonstrated that the Fgfr2 +/P253R mutation resulted in mice with cranial features that resemble those of the Fgfr2+/S252W mice and human Apert syndrome. Activated p38 in addition to the ERK1/2 signaling pathways may mediate the mutant neurocranial phenotype. Though Apert syndrome is traditionally thought to be a consistent phenotype, our results suggest localized and regional variations in the phenotypes that characterize Apert syndrome.