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In vivo function of versican : Analysis of knockin mice

多功能蛋白聚糖的体内功能：敲入小鼠的分析

基本信息

批准号：
17590361
负责人：
WATANABE Hideto
金额：
$ 2.3万
依托单位：
Aichi Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590361/
关键词：
versican PG-M proteoglycan extracellular matrix collagen TGFbeta BMP コラーゲン線維

项目摘要

We generated knockin mice whose versican lacks the A subdomain of the N-terminal G1 domain. The homozygotes expressed approximately 50% of the mutant versican with decreased incorporation in the extracellular matrix, and showed cardiac dilatation at E9.5 and died by E18.5. In contrast to the complete knockout mice of versican exhibiting severe cardiac malformation, the basic structure of the heart was formed in the kockin homozygotes. Analysis of the heart revealed impaired myocardial cell differentiation with downregulated BMP-signaling, and fibrosis of myocardial wall with up-regulated TGFbeta signaling (submitted).We investigated the role of versican in mesenchymal condensation of the cartilage primodium, using a chondrogenic cell line N1511, and found that chondroitin sulfate (CS) chains of versican facilitate chondrocyte differentiation (Kiamiya, N., et al., J Biol Chem, 2006).We analyzed versican present in the articular cartilage, and found that it is in the form of the proteoglycan aggregate with link protein and hyaluronan. CS of versican was much less sulfated than that of aggrecan (Matsumoto, K., et al., J Biol Chem, 2006).To date, six glycosyltransferases are known to be involved in CS biosynthesis. We attempted to determine the enzyme critical for CS synthesis in cartilage, and found that CS N-acetylgalactosaminyltransferase-1 plays a critical role in the synthesis (Sakai, K., et al., J Biol Chem, 2007).

我们产生了敲入小鼠，其多功能蛋白聚糖缺乏N-末端G1结构域的A亚结构域。纯合子表达约50%的突变型多功能蛋白聚糖，细胞外基质中的掺入减少，并在E9.5时显示心脏扩张，并在E18.5时死亡。与多功能蛋白聚糖基因完全敲除小鼠表现出严重的心脏畸形相反，在kockin纯合子中形成了心脏的基本结构。心脏的分析揭示了具有下调的BMP信号传导的受损的心肌细胞分化，以及具有上调的TGF β信号传导的心肌壁纤维化（提交）。我们使用软骨形成细胞系N1511研究了多功能蛋白聚糖在软骨原基的间充质凝聚中的作用，并发现多功能蛋白聚糖的硫酸软骨素（CS）链促进软骨细胞分化（Kiamiya，N.，例如，我们分析了存在于关节软骨中的多功能蛋白聚糖，发现它是以具有连接蛋白和透明质酸的蛋白聚糖聚集体的形式存在。多功能蛋白聚糖的CS比聚集蛋白聚糖的CS硫酸化少得多（松本，K.，例如，迄今为止，已知六种糖基转移酶参与CS生物合成。我们试图确定软骨中CS合成的关键酶，并发现CS N-乙酰半乳糖胺转移酶-1在合成中起关键作用（Sakai，K.，例如，J Biol Chem，2007）。