Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte maturation
Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte maturation
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DOI：
10.1038/ng1880
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发表时间：
2006-10-01
期刊：
影响因子：
30.8
通讯作者：
Knapik, Ela W.
中科院分区：
文献类型：
--
作者：
Lang, Michael R.;Lapierre, Lynne A.;Knapik, Ela W.
越来越多的人类疾病与分泌途径基因突变有关。化学诱导的斑马鱼破碎变体导致颅面骨骼畸形、胸鳍扭结和体长短。通过定位克隆，我们在 sec23a 基因中发现了一个将亮氨酸转化为终止密码子 (L402X) 的无义突变，sec23a 基因是 COPII 复合体的组成部分，对于内质网和高尔基体之间的顺行蛋白质运输至关重要。斑马鱼破碎突变体正常发育，直到颅面软骨形成开始。破碎软骨细胞在扩张的内质网中积累蛋白质，导致软骨细胞外基质 (ECM) 沉积物严重减少，包括 II 型胶原蛋白。我们证明旁系同源基因 sec23b 也是软骨细胞 ECM 分泌途径的重要组成部分。相比之下，COPI复合物的敲除不会阻碍颅面形态发生。由于 SEC23A 病变导致颅骨-豆状核-缝线发育不良综合征，Crusher 提供了第一个脊椎动物模型系统，将内质网生物学与高尔基体运输与临床相关的形态学联系起来。
An increasing number of human disorders have been linked to mutations in genes of the secretory pathway. The chemically induced zebrafish crusher variant results in malformed craniofacial skeleton, kinked pectoral fins and a short body length. By positional cloning, we identified a nonsense mutation converting leucine to a stop codon (L402X) in the sec23a gene, an integral component of the COPII complex, which is critical for anterograde protein trafficking between endoplasmic reticulum and Golgi apparatus. Zebrafish crusher mutants develop normally until the onset of craniofacial chondrogenesis. crusher chondrocytes accumulate proteins in a distended endoplasmic reticulum, resulting in severe reduction of cartilage extracellular matrix (ECM) deposits, including type II collagen. We demonstrate that the paralogous gene sec23b is also an essential component of the ECM secretory pathway in chondrocytes. In contrast, knockdown of the COPI complex does not hinder craniofacial morphogenesis. As SEC23A lesions cause the cranio-lenticulo-sutural dysplasia syndrome, crusher provides the first vertebrate model system that links the biology of endoplasmic reticulum to Golgi trafficking with a clinically relevant dysmorphology.