Aspects of achondroplasia in the skulls of dwarf transgenic mice: A cephalometric study
Aspects of achondroplasia in the skulls of dwarf transgenic mice: A cephalometric study
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DOI：
10.1002/ar.a.20308
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发表时间：
2006-03-01
期刊：
影响因子：
--
通讯作者：
Duke, PJ
中科院分区：
文献类型：
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作者：
Bloom, MW;Murakami, S;Duke, PJ
软骨发育不全是人类最常见的短肢侏儒症，由成纤维细胞生长因子受体3(FGFR3)基因的单核苷酸替换引起。FGFR3在一定程度上通过丝裂原活化蛋白激酶途径(MAPK)调节骨骼生长。为了研究这一途径在软骨细胞分化中的作用，建立了一种转基因小鼠，在软骨细胞中表达MEK1的结构性活性突变体，并表现出典型的人类软骨发育不全的矮小特征，即轴骨和附件骨缩短，面中部发育不良和穹顶状头盖骨。在这项研究中，对MEK1突变的头骨进行了头影测量，以确定MEK1小鼠是否是软骨发育不全的良好模型。在MEK1和对照组小鼠颅骨数字化X线片上测量颅骨长度、颅顶弧度、脑壳面积、最大直径和最小直径。在正中矢状面上测量颅底、鼻骨长度和枕大孔直径。数据通过除以每只动物体重的立方根来归一化。转基因小鼠的头骨呈穹顶状，面中部缺失，下颌骨(相对)突出，颅底和鼻骨比野生型小鼠短。转基因小鼠的头骨长度明显较短，但头骨弧度明显较大。在转基因小鼠中，脑壳更大、更圆，脑壳的最小直径明显更大。枕大孔前移，但未见狭窄。MEK1小鼠的头影测量证实这些小鼠是软骨发育不全的模型，表明MAP激酶信号通路参与了骨骼发育过程中的成纤维细胞生长因子信号传递。(C)2006年Wiley-Liss，Inc.
Achondroplasia, the most common short-limbed dwarfism in humans, results from a single nucleotide substitution in the gene for fibroblast growth factor receptor 3 (FGFR3). FGFR3 regulates bone growth in part via the mitogen-activated protein kinase pathway (MAPK). To examine the role of this pathway in chondrocyte differentiation, a transgenic mouse was generated that expresses a constitutively active mutant of MEK1 in chondrocytes and exhibits dwarfing characteristics typical of human achondroplasia, i.e., shortened axial and appendicular skeletons, mid-facial hypoplasia, and dome-shaped cranium. In this study, cephalometrics of the MEK1 mutant skulls were assessed to determine if the MEK1 mice are a good model of achondroplasia. Skull length, arc of the cranial vault, and area, maximum and minimum diameters of the brain case were measured on digitized radiographs of skulls of MEK1 and control mice. Cranial base and nasal bone length and foramen magnum diameter were measured on midsagittal micro-CT sections. Data were normalized by dividing by the cube root of each animal's weight. Transgenic mice exhibited a domed skull, deficient midface, and (relatively) prognathic mandible and had a shorter cranial base and nasal bone than the wild-type. Skull length was significantly less in transgenic mice, but cranial arc was significantly greater. The brain case was larger and more circular and minimum diameter of the brain case was significantly greater in transgenic mice. The foramen magnum was displaced anteriorly but not narrowed. MEK1 mouse cephalometrics confirm these mice as a model for achondroplasia, demonstrating that the MAP kinase signaling pathway is involved in FGF signaling in skeletal development. (c) 2006 Wiley-Liss, Inc.