FGFR2 IN SKELETOGENESIS--MUTATIONAL ANALYSIS IN MICE

FGFR2 在骨骼发生中的作用——小鼠突变分析

• 批准号: 6536320
• 负责人: HYUN-DUCK NAH-CEDERQUIST
• 金额: $ 7.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6536320
• 关键词: apoptosis; biological signal transduction; cell differentiation; cell growth regulation; cell proliferation; craniofacial; craniosynostosis; fibroblast growth factor; flow cytometry; gene mutation; gene targeting; genetically modified animals; growth factor receptors; histology; laboratory mouse; mitogen activated protein kinase; morphometry; normal ossification; osteoblasts; osteogenesis; phenotype; receptor expression; western blottings

DESCRIPTION: (Provided by Applicant) The development of the craniofacial skeleton with its interposed sutures involves a complex process, for which molecular and cellular regulatory mechanisms are not well understood. Recent genetic studies have linked various activating mutations in the fibroblast growth factor receptor 2 (FGFR2) gene to a subset of craniosynostosis syndromes, which have in common craniofacial skeletal deformities associated with the premature fusion of cranial sutures. This suggests that FGFR2 may play important roles in skeletal and sutural development. To further develop this notion, the investigators have introduced bone-targeted mFGFR2 transgene constructs, containing an activating mutation (Pro253Arg; an Apert mutation) or a dominant negative mutation, into the mouse germ line and generated several lines of transgenic mice. Initial analyses of these mice revealed that those with an activating mutation manifested some of the typical craniofacial features of craniosynostosis patients. The mice with a dominant negative mutation also displayed a variety of skeletal abnormalities, but they were distinctively different from the craniosynostosis phenotype. Based on pro- mitogenic and anti-apoptotic responses to FGF signaling in bone cells, the investigators hypothesize that an activating FGFR2 mutation promotes proliferation of osteoblasts, while suppressing apoptosis in these cells, resulting in uncontrolled bone formation and, ultimately, suture fusion. In contrast, loss of normal FGFR activities may result in reduced bone cell proliferation with an increased rate of apopotosis, culminating in dystrophic bone and wide-open sutures. To test their hypothesis, the investigators will define the skeletal and suture phenotypes of newly generated transgenic mouse lines (Aim 1), investigate how these mutations alter bone cell functions associated with osteogenesis and suture formation (Aim 2), and finally determine whether the mitogene activated protein (MAP) kinase pathway is involved in some of the altered bone cell functions induced by FGFR2 mutations (Aim 3). Data collected from this pilot study will be used to develop hypotheses to be tested in a larger research project.

描述：(申请人提供)头面部发育情况 骨骼及其中间缝合涉及一个复杂的过程，对于 分子和细胞调控机制还不是很清楚。近期 遗传学研究已经将成纤维细胞中的各种激活突变联系在一起 生长因子受体2(FGFR2)基因在颅脑融合症中的作用 常见的头面部骨骼畸形综合征 与颅缝过早融合有关。这表明FGFR2可能 在骨骼和缝合线的发育中起着重要作用。进一步发展 在这个概念上，研究人员引入了骨靶向mFGFR2转基因 包含激活突变的构建体(Pro253Arg；Apert突变) 或显性负突变，进入小鼠生殖系并产生 几个转基因小鼠的品系。对这些老鼠的初步分析显示， 那些有激活突变的人表现出一些典型的头面部 颅缝早闭患者的特点。带有显性负值的小鼠 突变还表现出各种骨骼异常，但它们是 与颅缝融合症的表型明显不同。基于PRO- 骨细胞对成纤维细胞生长因子信号的促有丝分裂和抗凋亡反应 研究人员假设，激活的FGFR2突变促进 成骨细胞的增殖，同时抑制这些细胞的凋亡， 导致失控的骨形成，最终导致缝合融合。在……里面 相比之下，正常FGFR活性的丧失可能会导致骨细胞减少 随着细胞凋亡率的增加而增殖，最终导致营养不良 骨头和大口缝合线。为了验证他们的假设，调查人员将 确定新产生的转基因小鼠的骨骼和缝合表型 LINES(目标1)，研究这些突变如何改变骨细胞功能 与成骨和缝合形成有关(目标2)，最后 确定丝裂原活化蛋白(MAP)激酶途径是否 参与FGFR2突变引起的某些骨细胞功能改变 (目标3)。从这项初步研究中收集的数据将用于开发 假设将在一个更大的研究项目中进行测试。

项目成果

Activating (P253R, C278F) and dominant negative mutations of FGFR2: Differential effects on calvarial bone cell proliferation, differentiation, and mineralization

• DOI: 10.1080/03008200390181799
• 发表时间: 2003-01-01
• 期刊: CONNECTIVE TISSUE RESEARCH
• 影响因子: 2.9
• 作者: Ratisoontorn, C;Fan, GF;Nah, HD
• 通讯作者: Nah, HD