Functional analysis of zebrafish microfibril-associated glycoprotein-1 (Magp 1) in vivo reveals roles for microfibrils in vascular development and function
Functional analysis of zebrafish microfibril-associated glycoprotein-1 (Magp 1) in vivo reveals roles for microfibrils in vascular development and function
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DOI：
10.1182/blood-2005-02-0789
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发表时间：
2006-06-01
期刊：
影响因子：
20.3
通讯作者：
Ekker, Stephen C.
中科院分区：
文献类型：
--
作者：
Chen, Eleanor;Larson, Jon D.;Ekker, Stephen C.
突变的马凡氏综合征（Marfan syndrome），证明微纤维在血管结构和功能的关键要求。然而，许多微纤维相关分子的身份和功能，血管发育和功能所必需的尚未得到表征。在我们基于吗啉代的筛选血管发育所需的分泌组成员中，我们确定了斑马鱼胚胎发生中微纤维形成的关键参与者。微原纤维相关糖蛋白1（Microfibril-associated glycoprotein-1，MAGP 1）是一种存在于哺乳动物和斑马鱼微原纤维中的保守蛋白。在产生微纤维的细胞中检测到magp 1 mRNA的表达。功能性Magp 1-mRFP融合蛋白的分析揭示了胚胎发生期间沿着中线和脉管系统中的定位沿着。低表达和过表达分析表明，特定的Magp 1蛋白水平是血管发育的关键。整合素的功能是妥协的magp 1 morphant胚胎，这表明减少整合素-基质相互作用是血管缺陷的magp 1 morphant的主要机制。我们进一步表明，Magp 1和Escherin-1在体内相互作用。这项研究表明，MAGP 1是微纤维形成和发育过程中完整性的关键参与者。MAGP 1在血管形态发生和功能中的重要作用也支持广泛的临床应用，包括血管疾病和心血管组织工程中的治疗靶点。
Mutations in fibrillin-1 (FBN1) result in Marfan syndrome, demonstrating a critical requirement for microfibrils in vessel structure and function. However, the identity and function of many microfibril-associated molecules essential for vascular development and function have yet to be characterized. In our morpholino-based screen for members of the secretome required for vascular development, we identified a key player in microfibril formation in zebrafish embryogenesis. Microfibril-associated glycoprotein-1 (MAGP1) is a conserved protein found in mammalian and zebrafish microfibrils. Expression of magp1 mRNA is detected in microfibril-producing cells. Analysis of a functional Magp1-mRFP fusion protein reveals localization along the midline and in the vasculature during embryogenesis. Underexpression and overexpression analyses demonstrate that specific Magp1 protein levels are critical for vascular development. Integrin function is compromised in magp1 morphant embryos, suggesting that reduced integrin-matrix interaction is the main mechanism for the vascular defects in magp1 morphants. We further show that Magp1 and fibrillin-1 interact in vivo. This study implicates MAGP1 as a key player in microfibril formation and integrity during development. The essential role for MAGP1 in vascular morphogenesis and function also supports a wide range of clinical applications, including therapeutic targets in vascular disease and cardiovascular tissue engineering.