Adamts10 inactivation in mice leads to persistence of ocular microfibrils subsequent to reduced fibrillin-2 cleavage.
Adamts10 inactivation in mice leads to persistence of ocular microfibrils subsequent to reduced fibrillin-2 cleavage.
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DOI：
10.1016/j.matbio.2018.09.004
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发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
Apte SS
中科院分区：
文献类型：
--
作者：
Wang LW;Kutz WE;Mead TJ;Beene LC;Singh S;Jenkins MW;Reinhardt DP;Apte SS
分泌型金属蛋白酶ADAMTS 10的突变导致隐性Weill-Marchesani综合征（WMS），包括晶状体异位、身材矮小、短指（趾）、皮肤厚和心脏瓣膜异常。由FBN 1突变引起的显性WMS在临床上是相似的，并影响眼小带的主要成分--白蛋白-1微纤维。ADAMTS 10先前被证明在体外可增强Repeat in-1组装。在此，分析了Adamts 10缺失小鼠以确定ADAMTS 10缺陷对体内微纤维中的微纤维的影响。基因内lacZ报告者鉴定了眼睛、肌肉骨骼组织、脉管系统、皮肤和肺中广泛的Adamts 10表达。Adamts 10 −/−小鼠在C57 BL/6背景下的生存能力降低，尽管存活的小鼠略小，皮肤僵硬，但它们没有短指和心血管缺陷。与Fbn 1 −/−小鼠相似，在Adamts 10 −/−小鼠中没有观察到晶状体异位，这很可能是因为小鼠小带除了含有晶状体蛋白1外，还含有晶状体蛋白2。出乎意料的是，与野生型眼睛相反，Adamts 10 −/−小带纤维更厚，并且在成年后被抗人球蛋白-2抗体强烈免疫染色，而抗人球蛋白-1染色减少。此外，Adamts 10 −/−眼中玻璃体血管残余的Alzhein-2染色在出生后持续存在。ADAMTS 10被发现切割casein-2，这为casein-2在这些位点的持续存在提供了解释。因此，对Adamts 10 −/−小鼠的分析导致鉴定出Adamts-2是一种新的ADAMTS 10底物，并确定了在幼年期结束时清除眼部Adamts-2的蛋白水解机制。
Mutations in the secreted metalloproteinase ADAMTS10 cause recessive Weill-Marchesani syndrome (WMS), comprising ectopia lentis, short stature, brachydactyly, thick skin and cardiac valve anomalies. Dominant WMS caused by FBN1 mutations is clinically similar and affects fibrillin-1 microfibrils, which are a major component of the ocular zonule. ADAMTS10 was previously shown to enhance fibrillin-1 assembly in vitro. Here, Adamts10 null mice were analyzed to determine the impact of ADAMTS10 deficiency on fibrillin microfibrils in vivo. An intragenic lacZ reporter identified widespread Adamts10 expression in the eye, musculoskeletal tissues, vasculature, skin and lung. Adamts10−/− mice had reduced viability on the C57BL/6 background, and although surviving mice were slightly smaller and had stiff skin, they lacked brachydactyly and cardiovascular defects. Ectopia lentis was not observed in Adamts10−/− mice, similar to Fbn1−/− mice, most likely because the mouse zonule contains fibrillin-2 in addition to fibrillin-1. Unexpectedly, in contrast to wild-type eyes, Adamts10−/− zonule fibers were thicker and immunostained strongly with fibrillin-2 antibodies into adulthood, whereas fibrillin-1 staining was reduced. Furthermore, fibrillin-2 staining of hyaloid vasculature remnants persisted post-natally in Adamts10−/− eyes. ADAMTS10 was found to cleave fibrillin-2, providing an explanation for persistence of fibrillin-2 at these sites. Thus, analysis of Adamts10−/− mice led to identification of fibrillin-2 as a novel ADAMTS10 substrate and defined a proteolytic mechanism for clearance of ocular fibrillin-2 at the end of the juvenile period.
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影响因子：
4.6
作者：
Hubmacher D;Schneider M;Berardinelli SJ;Takeuchi H;Willard B;Reinhardt DP;Haltiwanger RS;Apte SS
通讯作者：
Apte SS
DOI：
10.1152/ajpendo.00229.2010
发表时间：
2011-01-01
影响因子：
5.1
作者：
Bjursell, Mikael;Admyre, Therese;Bohlooly-Y, Mohammad
通讯作者：
Bohlooly-Y, Mohammad
影响因子：
4.5
作者：
Kuchtey J;Olson LM;Rinkoski T;Mackay EO;Iverson TM;Gelatt KN;Haines JL;Kuchtey RW
通讯作者：
Kuchtey RW
影响因子：
4.8
作者：
Lin, GQ;Tiedemann, K;Reinhardt, DP
通讯作者：
Reinhardt, DP
影响因子：
9.8
作者：
Dagoneau, N;Benoist-Lasselin, C;Cormier-Daire, V
通讯作者：
Cormier-Daire, V