Mice deficient in Ext2 lack heparan sulfate and develop exostoses
Mice deficient in Ext2 lack heparan sulfate and develop exostoses
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DOI：
10.1242/dev.02088
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发表时间：
2005-11-01
期刊：
影响因子：
4.6
通讯作者：
Werb, Z
中科院分区：
文献类型：
--
作者：
Stickens, D;Zak, BM;Werb, Z
遗传性多发性外生骨疣（HME）是一种遗传异质性的人类疾病，其特征是长骨末端附近的骨生长。HME由EXT 1和EXT 2中的突变引起，EXT 1和EXT 2是编码合成硫酸乙酰肝素链的糖基转移酶的基因。为了研究疾病与这些基因突变的关系，我们通过基因靶向产生了Ext 2缺失小鼠。纯合子突变胚胎发育正常，直到胚胎第6.0天，当他们成为生长停滞，未能原肠胚，硫酸乙酰肝素在胚胎发育早期的重要作用。杂合子有正常的寿命和生育能力;然而，对它们骨骼的分析表明，大约三分之一的动物形成了一个或多个异位骨生长（外生骨疣）。值得注意的是，所有的小鼠都表现出软骨分化的多种异常，包括长骨中软骨细胞的解体和肋软骨的过早肥大。这些变化并不归因于刺猬信号传导的缺陷，这表明它们是由其他硫酸乙酰肝素依赖性途径的缺陷引起的。单倍不足触发软骨分化异常的发现，使我们深入了解外生骨疣发生的复杂分子机制。
Hereditary multiple exostoses (HME) is a genetically heterogeneous human disease characterized by the development of bony outgrowths near the ends of long bones. HME results from mutations in EXT1 and EXT2, genes that encode glycosyltransferases that synthesize heparan sulfate chains. To study the relationship of the disease to mutations in these genes, we generated Ext2-null mice by gene targeting. Homozygous mutant embryos developed normally until embryonic day 6.0, when they became growth arrested and failed to gastrulate, pointing to the early essential role for heparan sulfate in developing embryos. Heterozygotes had a normal lifespan and were fertile; however, analysis of their skeletons showed that about one-third of the animals formed one or more ectopic bone growths (exostoses). Significantly, all of the mice showed multiple abnormalities in cartilage differentiation, including disorganization of chondrocytes in long bones and premature hypertrophy in costochondral cartilage. These changes were not attributable to a defect in hedgehog signaling, suggesting that they arise from deficiencies in other heparan sulfate-dependent pathways. The finding that haploinsufficiency triggers abnormal cartilage differentiation gives insight into the complex molecular mechanisms underlying the development of exostoses.