Chen L, Li C, Qiao W, Xu X, Deng C
Genetics of Development and Disease Branch, Building 10, Room 9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Hum Mol Genet. 2001 Mar 1;10(5):457-65. doi: 10.1093/hmg/10.5.457.
Missense mutations in fibroblast growth factor receptor 3 (FGFR3) result in several types of human skeletal dysplasia, including the neonatally lethal dwarfism known as thanatophoric dysplasia. An engineered Ser(365)-->Cys substitution in mouse FGFR3, which is equivalent to a mutation associated with thanatophoric dysplasia-I in humans, has now been shown to cause severe dwarfism but not neonatal death. The mutant mice exhibit shortened limbs as a result of markedly reduced proliferation and impaired differentiation of growth plate chondrocytes. The receptor-activating mutation also resulted in downregulation of expression of the Indian hedgehog (IHH) and parathyroid hormone-related protein (PTHrP) receptor genes, both of which are important for bone growth. Interactions between FGFR3- and PTHrP-receptor-mediated signals during endochondral ossification were examined with embryonic metatarsal bones maintained in culture under defined conditions. Consistent with the in vivo observations, FGF2 inhibited bone growth in culture and induced downregulation of IHH and PTHrP receptor gene expression. Furthermore, PTHrP partially reversed the inhibition of long bone growth caused by activation of FGFR3; however, it impaired the differentiation of chondrocytes in an FGFR3-independent manner. These observations suggest that FGFR3 and IHH-PTHrP signals are transmitted by two interacting parallel pathways that mediate both overlapping and distinct functions during endochondral ossification.
成纤维细胞生长因子受体3（FGFR3）的错义突变会导致多种类型的人类骨骼发育不良，包括新生儿致死性侏儒症，即致死性骨发育不全。现已证明，小鼠FGFR3中一种人工构建的Ser(365)-->Cys替换，相当于人类中与致死性骨发育不全I型相关的一种突变，会导致严重侏儒症，但不会导致新生儿死亡。由于生长板软骨细胞的增殖明显减少和分化受损，突变小鼠表现出四肢缩短。受体激活突变还导致印度刺猬因子（IHH）和甲状旁腺激素相关蛋白（PTHrP）受体基因的表达下调，这两种基因对骨骼生长都很重要。在特定条件下，用培养的胚胎跖骨研究了软骨内骨化过程中FGFR3和PTHrP受体介导的信号之间的相互作用。与体内观察结果一致，FGF2在培养中抑制骨生长，并诱导IHH和PTHrP受体基因表达下调。此外，PTHrP部分逆转了FGFR3激活引起的长骨生长抑制；然而，它以FGFR3非依赖的方式损害软骨细胞的分化。这些观察结果表明，FGFR3和IHH-PTHrP信号通过两条相互作用的平行途径传递，这两条途径在软骨内骨化过程中介导重叠和不同的功能。
