Bloom Melissa Wadler, Murakami Shunichi, Cody Dianna, Montufar-Solis Dina, Duke Pauline Jackie
Department of Orthodontics, Dental Branch, University of Texas Health Science Center, Houston, Texas 77030, USA.
Anat Rec A Discov Mol Cell Evol Biol. 2006 Mar;288(3):316-22. doi: 10.1002/ar.a.20308.
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.
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）基因中的单核苷酸替换引起。FGFR3部分通过丝裂原活化蛋白激酶途径（MAPK）调节骨骼生长。为了研究该途径在软骨细胞分化中的作用，构建了一种转基因小鼠，其在软骨细胞中表达组成型活性的MEK1突变体，并表现出人类软骨发育不全典型的侏儒特征，即轴向和附属骨骼缩短、面中部发育不全和圆顶形颅骨。在本研究中，对MEK1突变体颅骨进行了头影测量，以确定MEK1小鼠是否是软骨发育不全的良好模型。在MEK1小鼠和对照小鼠颅骨的数字化X线片上测量颅骨长度、颅顶弧以及脑壳的面积、最大和最小直径。在矢状面显微CT切片上测量颅底和鼻骨长度以及枕骨大孔直径。数据通过除以每只动物体重的立方根进行标准化。转基因小鼠表现出圆顶形颅骨、面中部缺陷和（相对）前突的下颌骨，并且颅底和鼻骨比野生型短。转基因小鼠的颅骨长度明显较短，但颅弧明显较长。转基因小鼠的脑壳更大且更呈圆形，脑壳的最小直径明显更大。枕骨大孔向前移位但未变窄。MEK1小鼠的头影测量结果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中的FGF信号传导。
