A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors
A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors
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DOI：
10.1093/hmg/8.1.35
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发表时间：
1999-01-01
影响因子：
3.5
通讯作者：
Deng, CX
中科院分区：
文献类型：
--
作者：
Li, CL;Chen, L;Deng, CX
人成纤维细胞生长因子受体3(FGFR3)错义突变导致多种骨骼发育不良，包括软骨发育不良、软骨发育不良和死亡发育不良。为了研究FGFR3在骨生长中的作用，并为FGFR3相关的遗传性骨骼疾病建立动物模型，我们使用敲入方法将一个点突变(Lys644Glu)引入到小鼠FGFR3基因组中。我们发现，Lys644Glu突变导致软骨内骨生长迟缓，其严重程度与突变的FGFR3的表达水平直接相关，突变杂合小鼠(FGFR3(Td/+))的表达水平接近野生型的20%，并表现出轻度的骨发育不良。然而，当突变等位基因的拷贝数从1(FGFR3(Td/+))增加到2(FGFR3(Td/Td))时，骨生长迟缓变得更加严重，表现为类似软骨发育不全患者的表型，其特征是生长板软骨增殖显著减少，长骨大头和短缩，长骨变短最明显的部位是股骨。分子分析表明，突变受体的表达导致STAT1、Stat5a和Stat5b的激活，以及p16、p18和p19细胞周期抑制因子的上调，导致软骨细胞休止区的急剧扩张，以牺牲增殖的软骨细胞为代价。因此，突变的生长板处于较不活跃的状态，产生的成熟和肥大的软骨细胞较少。这些数据提供了直接的遗传学证据，表明FGFR3的点突变导致人类骨骼发育不良，并揭示了FGFR3信号通过调节Stats和INK4细胞周期抑制物的表达来调节骨生长的机制。
Missense mutations of human fibroblast growth factor receptor 3 (FGFR3) result in several skeletal dysplasias, including hypochondroplasia, achondroplasia and thanatophoric dysplasia. To study the function of FGFR3 in bone growth and to create animal models for the FGFR3-related inherited skeletal disorders, we introduced a point mutation (Lys644Glu) into the murine FGFR3 genome using a knock-in approach. We found that the Lys644Glu mutation resulted in retarded endochondral bone growth with severity directly linked to the expression level of the mutated Fgfr3, Mice heterozygous for the mutation (Fgfr3(TD/+)) expressed the mutant allele at similar to 20% of the wild-type level and exhibited a mild bone dysplasia, However, when the copy number of the mutant allele increased from one (Fgfr3(TD/+)) to two (Fgfr3(TD/TD)), the retardation of bone growth became more severe and showed phenotypes resembling those of achondroplasia patients, characterized by a dramatically reduced proliferation of growth plate cartilage, macrocephaly and shortening of the long bones, which was most pronounced in the femur. Molecular analysis revealed that expression of the mutant receptor caused the activation of Stat1, Stat5a and Stat5b, and the up-regulation of p16, p18 and p19 cell cycle inhibitors, leading to dramatic expansion of the resting zone of chondrocytes at the expense of the proliferating chondrocytes. The mutant growth plates consequently were in a less active state and generated fewer maturing and hypertrophic chondrocytes. These data provide direct genetic evidence that the point mutations in FGFR3 cause human skeletal dysplasias and uncover a mechanism through which the FGFR3 signals regulate bone growth by modulating expression of Stats and ink4 cell cycle inhibitors.