In vivo function of versican : Analysis of knockin mice

我们产生了敲门小鼠，其Verscan缺乏N-末端G1结构域的A亚域。纯合子表达了大约50%的突变Verscan，并减少了对细胞外基质的掺入，在E9.5表现出心脏扩张，并在E18.5死亡。与表现出严重心脏畸形的完全基因敲除小鼠不同，心脏的基本结构是在kockin纯合子中形成的。对心脏的分析显示心肌细胞分化受损，BMP信号下调，心肌壁纤维化，TGFβ信号上调(提交)。我们使用软骨细胞系N1511研究了万西康在软骨原基间充质凝聚中的作用，发现万西康的硫酸软骨素(CS)链促进了软骨细胞的分化(Kiamiya，N.，等，J Biol Chem，2006)。我们分析了万西康存在于关节软骨中，发现它是以蛋白多糖与连接蛋白和透明质酸聚集的形式存在的。Verscan的CS的硫酸盐化程度远低于aggrecan(MatSumoto，K.，et al.，J Biol Chem，2006)。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.，等，J Biol Chem，2007)。

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).