Deformed Skull Morphology Is Caused by the Combined Effects of the Maldevelopment of Calvarias, Cranial Base and Brain in FGFR2-P253R Mice Mimicking Human Apert Syndrome.
Deformed Skull Morphology Is Caused by the Combined Effects of the Maldevelopment of Calvarias, Cranial Base and Brain in FGFR2-P253R Mice Mimicking Human Apert Syndrome.
复制标题
模拟人类阿珀特综合征的 FGFR2-P253R 小鼠颅骨、颅底和大脑发育不良共同影响导致颅骨形态畸形
DOI：
10.7150/ijbs.16287
复制
发表时间：
2017
影响因子：
9.2
通讯作者：
Du X
中科院分区：
文献类型：
--
作者：
Luo F;Xie Y;Xu W;Huang J;Zhou S;Wang Z;Luo X;Liu M;Chen L;Du X
Apert综合征（AS）是一种以颅缝闭合为特征的常见遗传综合征。Apert患者和小鼠模型均出现缝合线、颅底和脑的异常，这些异常可能参与了Apert综合征颅骨畸形的发病机制。为了区分这些头部成分在AS异常颅骨形态发病机制中的不同作用，我们通过将FGFR2 +/P253R-Neo小鼠分别与Col2a1-Cre、骨钙素- cre （OC-Cre）和netin - cre小鼠杂交，产生了在软骨细胞、成骨细胞和中枢神经系统（CNS）祖细胞中特异性表达突变FGFR2的小鼠品系。然后，我们使用欧几里得距离矩阵分析（EDMA），通过微ct和微mri定量分析这些突变小鼠的颅骨和脑形态。Col2a1-Fgfr2+/P253R小鼠颅骨表现出Apert综合征样畸形，如沿头尾轴颅骨尺寸缩短，鼻骨缩短，颅底联合软骨明显提前骨化。OC-Fgfr2+/P253R小鼠在8周时出现面部畸形。巢蛋白- fgfr2 +/P253R小鼠在8周时显示出尾部颅骨和脑的背腹高度和背尾长度增加。我们的研究表明，AS的颅骨形态异常是颅骨、颅底和脑组织发育不良共同作用的结果。这些发现进一步加深了我们对AS颅骨形态异常的发病机制的认识，并为进一步分析AS的颅骨表型和临床治疗提供了新的线索。
Apert syndrome (AS) is a common genetic syndrome in humans characterized with craniosynostosis. Apert patients and mouse models showed abnormalities in sutures, cranial base and brain, that may all be involved in the pathogenesis of skull malformation of Apert syndrome. To distinguish the differential roles of these components of head in the pathogenesis of the abnormal skull morphology of AS, we generated mouse strains specifically expressing mutant FGFR2 in chondrocytes, osteoblasts, and progenitor cells of central nervous system (CNS) by crossing Fgfr2+/P253R-Neo mice with Col2a1-Cre, Osteocalcin-Cre (OC-Cre), and Nestin-Cre mice, respectively. We then quantitatively analyzed the skull and brain morphology of these mutant mice by micro-CT and micro-MRI using Euclidean distance matrix analysis (EDMA). Skulls of Col2a1-Fgfr2+/P253R mice showed Apert syndrome-like dysmorphology, such as shortened skull dimensions along the rostrocaudal axis, shortened nasal bone, and evidently advanced ossification of cranial base synchondroses. The OC-Fgfr2+/P253R mice showed malformation in face at 8-week stage. Nestin-Fgfr2+/P253R mice exhibited increased dorsoventral height and rostrocaudal length on the caudal skull and brain at 8 weeks. Our study indicates that the abnormal skull morphology of AS is caused by the combined effects of the maldevelopment in calvarias, cranial base, and brain tissue. These findings further deepen our knowledge about the pathogenesis of the abnormal skull morphology of AS, and provide new clues for the further analyses of skull phenotypes and clinical management of AS.