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The function of fibroblast growth factor receptor 2 during skeletal development and pathogenesis.

机译:成纤维细胞生长因子受体2在骨骼发育和发病机理中的功能。

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摘要

Fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling plays important roles during skeletal development. Fgfrs 1–3 are differentially expressed throughout developing bone. Fgfr1 and 2 are expressed by osteoblasts in the perichondrium/periosteum and Fgfr3 is expressed by proliferating chondrocytes in the growth plate. The importance has also been illustrated by genetic studies of human skeletal disorders. Human chondrodysplasia and craniosynostosis syndromes, result from activating or neomorphic mutations FGFR 1–3.; Apert syndrome (AS) is one of the most severe craniosynostosis syndrome and is associated with severe syndactyly of the hands and feet. AS is caused by specific missense mutations in one of two adjacent amino acid residues (S252W or P253R) in the highly conserved region linking immunoglobulin-like (Ig-like) domains II and III of FGFR2. AS mutations were introduced into the the full-length Fgfr2 cDNA and the function of AS mutant FGFR2 was examined in vitro. The results showed that AS mutations eliminated Fgfr2 splice form-specific ligand-binding specificity, which is essential for the paracrine signaling between epithelium and mesenchyme. The data suggest that the severe phenotypes of AS likely result from ectopic ligand-dependent activation of FGFR2.; To address the role of FGFR2 in normal bone development, a conditional gene deletion approach was adopted to overcome the early embryonic lethality of homozygous null mutations in Fgfr2. Inactivation of a floxed Fgfr2 allele with Dermol-CRE, which disrupted Fgfr2 in the osteoblast lineage, resulted in mice with skeletal dwarfism and decreased bone density. Although differentiation of the osteoblast lineage was not disturbed, the proliferation of osteoprogenitors and the anabolic function of mature osteoblasts were severely affected. These studies demonstrate that the osteoblast lineage requires multiple effectors to fulfill their function in bone formation.
机译:成纤维细胞生长因子(FGF)-FGF受体(FGFR)信号传导在骨骼发育过程中起重要作用。 Fgfrs 1-3在整个发育中的骨骼中差异表达。 Fgfr1 2 由软骨细胞/骨膜中的成骨细胞表达,而 Fgfr3 由生长平板中的软骨细胞增殖表达。人体骨骼疾病的遗传研究也说明了这一重要性。人类软骨发育不良和颅突增生综合征,是由于FGFR 1-3的激活或新突变引起的。 Apert综合征(AS)是最严重的颅突融合症之一,与手脚严重综合征相关。 AS是由在连接FGFR2的免疫球蛋白样(Ig样)域II和III的高度保守区域中两个相邻氨基酸残基之一(S252W或P253R)中的特定错义突变引起的。将AS突变引入全长 Fgfr2 cDNA中,并在体外检查了AS突变体FGFR2的功能。结果表明,AS突变消除了 Fgfr2 剪接形式特异性配体结合特异性,这对于上皮与间充质之间的旁分泌信号传导至关重要。数据表明,AS的严重表型可能是由FGFR2的异位配体依赖性激活引起的。为了研究FGFR2在正常骨骼发育中的作用,采用条件基因删除方法来克服 Fgfr2 中纯合无效突变的早期胚胎致死性。用 Dermol -CRE失活的 Fgfr2 等位基因会破坏成骨细胞谱系中的 Fgfr2 ,导致小鼠出现骨骼侏儒症并降低骨密度。尽管不破坏成骨细胞谱系的分化,但是严重影响了成骨祖细胞的增殖和成熟成骨细胞的合成代谢功能。这些研究表明,成骨细胞谱系需要多个效应子来发挥其在骨形成中的功能。

著录项

  • 作者

    Yu, Kai.;

  • 作者单位

    Washington University.;

  • 授予单位 Washington University.;
  • 学科 Biology Molecular.; Health Sciences Pathology.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 144 p.
  • 总页数 144
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;病理学;
  • 关键词

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