Klüppel Michael, Wight Thomas N, Chan Christina, Hinek Aleksander, Wrana Jeffrey L
Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
Development. 2005 Sep;132(17):3989-4003. doi: 10.1242/dev.01948. Epub 2005 Aug 3.
Glycosaminoglycans (GAGs) such as heparan sulfate and chondroitin sulfate are polysaccharide chains that are attached to core proteins to form proteoglycans. The biosynthesis of GAGs is a multistep process that includes the attachment of sulfate groups to specific positions of the polysaccharide chains by sulfotransferases. Heparan-sulfate and heparan sulfate-sulfotransferases play important roles in growth factor signaling and animal development. However, the biological importance of chondroitin sulfation during mammalian development and growth factor signaling is poorly understood. We show that a gene trap mutation in the BMP-induced chondroitin-4-sulfotransferase 1 (C4st1) gene (also called carbohydrate sulfotransferase 11 - Chst11), which encodes an enzyme specific for the transfer of sulfate groups to the 4-O-position in chondroitin, causes severe chondrodysplasia characterized by a disorganized cartilage growth plate as well as specific alterations in the orientation of chondrocyte columns. This phenotype is associated with a chondroitin sulfation imbalance, mislocalization of chondroitin sulfate in the growth plate and an imbalance of apoptotic signals. Analysis of several growth factor signaling pathways that are important in cartilage growth plate development showed that the C4st1(gt/gt) mutation led to strong upregulation of TGFbeta signaling with concomitant downregulation of BMP signaling, while Indian hedgehog (Ihh) signaling was unaffected. These results show that chondroitin 4-O-sulfation by C4st1 is required for proper chondroitin sulfate localization, modulation of distinct signaling pathways and cartilage growth plate morphogenesis. Our study demonstrates an important biological role of differential chondroitin sulfation in mammalian development.
硫酸乙酰肝素和硫酸软骨素等糖胺聚糖（GAGs）是连接在核心蛋白上形成蛋白聚糖的多糖链。GAGs的生物合成是一个多步骤过程，包括硫酸转移酶将硫酸基团连接到多糖链的特定位置。硫酸乙酰肝素和硫酸乙酰肝素硫酸转移酶在生长因子信号传导和动物发育中发挥重要作用。然而，硫酸软骨素硫酸化在哺乳动物发育和生长因子信号传导过程中的生物学重要性却知之甚少。我们发现，骨形态发生蛋白诱导的软骨素-4-硫酸转移酶1（C4st1）基因（也称为碳水化合物硫酸转移酶11 - Chst11）中的基因陷阱突变会导致严重的软骨发育不良，其特征是软骨生长板紊乱以及软骨细胞柱方向的特定改变。这种表型与硫酸软骨素硫酸化失衡、硫酸软骨素在生长板中的定位错误以及凋亡信号失衡有关。对软骨生长板发育中重要的几种生长因子信号通路的分析表明，C4st1(gt/gt)突变导致TGFβ信号强烈上调，同时BMP信号下调，而印度刺猬（Ihh）信号不受影响。这些结果表明，C4st1介导的软骨素4-O-硫酸化对于硫酸软骨素的正确定位、不同信号通路的调节以及软骨生长板形态发生是必需的。我们的研究证明了硫酸软骨素硫酸化差异在哺乳动物发育中的重要生物学作用。
