Sec24D-dependent transport of extracellular matrix proteins is required for zebrafish skeletal morphogenesis.
Sec24D-dependent transport of extracellular matrix proteins is required for zebrafish skeletal morphogenesis.
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DOI：
10.1371/journal.pone.0010367
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发表时间：
2010-04-28
期刊：
影响因子：
3.7
通讯作者：
Knapik EW
中科院分区：
文献类型：
--
作者：
Sarmah S;Barrallo-Gimeno A;Melville DB;Topczewski J;Solnica-Krezel L;Knapik EW
蛋白质从内质网（ER）到高尔基体的运输主要是通过被包被的囊泡载体（如COPII）进行的。在这里，我们描述了斑马鱼牛头犬突变破坏货物适配器Sec24D的功能，Sec24D是COPII复合体的一个组成部分。我们发现Sec24D对于软骨基质蛋白的分泌是必需的，而颅面原基和软骨前凝聚的前期发育并不依赖于这个亚型。牛头犬软骨细胞不能向细胞外基质（ECM）分泌II型胶原和基质，但膜结合受体β1-整合素和钙粘蛋白似乎以sec24d独立的方式离开内质网。因此，尽管电子显微镜和NBD c6 -神经酰胺染色显示，一部分内质网室和高尔基复合物具有功能，但sec24d缺陷细胞在膨胀的内质网中积累蛋白质。与内质网中蛋白质的积压一致，软骨细胞激活内质网应激反应机制并显著上调BiP转录。ECM分泌的失败阻碍了成软骨嵌入，从而导致小而畸形的软骨和严重的颅面畸形。这种缺陷是Sec24D突变体所特有的，因为Sec24C （Sec24D的近亲）的敲除不会导致颅面软骨畸形。然而，双Sec24C/ sec24d缺陷动物的颅面发育比牛头犬/sec24d更早停止，这表明Sec24C可以在软骨形成的初始阶段弥补sec24d的缺失，但sec24d对于软骨细胞成熟是必不可少的。我们的研究首次提出了Sec24D功能的发育观点，并确立了Sec24D作为软骨维持疾病和颅面出生缺陷的强有力候选基因。
Protein transport from endoplasmic reticulum (ER) to Golgi is primarily conducted by coated vesicular carriers such as COPII. Here, we describe zebrafish bulldog mutations that disrupt the function of the cargo adaptor Sec24D, an integral component of the COPII complex. We show that Sec24D is essential for secretion of cartilage matrix proteins, whereas the preceding development of craniofacial primordia and pre-chondrogenic condensations does not depend on this isoform. Bulldog chondrocytes fail to secrete type II collagen and matrilin to extracellular matrix (ECM), but membrane bound receptor β1-Integrin and Cadherins appear to leave ER in Sec24D-independent fashion. Consequently, Sec24D-deficient cells accumulate proteins in the distended ER, although a subset of ER compartments and Golgi complexes as visualized by electron microscopy and NBD C6-ceramide staining appear functional. Consistent with the backlog of proteins in the ER, chondrocytes activate the ER stress response machinery and significantly upregulate BiP transcription. Failure of ECM secretion hinders chondroblast intercalations thus resulting in small and malformed cartilages and severe craniofacial dysmorphology. This defect is specific to Sec24D mutants since knockdown of Sec24C, a close paralog of Sec24D, does not result in craniofacial cartilage dysmorphology. However, craniofacial development in double Sec24C/Sec24D-deficient animals is arrested earlier than in bulldog/sec24d, suggesting that Sec24C can compensate for loss of Sec24D at initial stages of chondrogenesis, but Sec24D is indispensable for chondrocyte maturation. Our study presents the first developmental perspective on Sec24D function and establishes Sec24D as a strong candidate for cartilage maintenance diseases and craniofacial birth defects.
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