Latent TGF-β binding protein 2 and 4 have essential overlapping functions in microfibril development.
Latent TGF-β binding protein 2 and 4 have essential overlapping functions in microfibril development.
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DOI：
10.1038/srep43714
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发表时间：
2017-03-02
影响因子：
4.6
通讯作者：
Nakamura T
中科院分区：
文献类型：
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作者：
Fujikawa Y;Yoshida H;Inoue T;Ohbayashi T;Noda K;von Melchner H;Iwasaka T;Shiojima I;Akama TO;Nakamura T
微纤维是弹性纤维组装和悬浮晶状体所必需的细胞外基质组分。我们以前报道过，潜伏性TGF-β结合蛋白2（LTBP-2），一种微纤维相关蛋白，是睫状小带中形成稳定微纤维束所必需的。然而，目前尚不清楚为什么Ltbp 2基因敲除小鼠仅表现出眼睛特异性表型，而LTBP-2在野生型小鼠中含有微纤维的其他组织中大量表达。在这里，我们表明，LTBP-4，另一种微纤维相关蛋白，弥补了LTBP-2在微纤维形成的损失。Ltbp 2/4S双敲除（DKO）小鼠由于肺气肿而表现出增加的致死率，这比在Ltbp 4S敲除小鼠中发现的严重得多。Ltbp 2/4S DKO小鼠肺中的弹性纤维严重紊乱和破碎。来自Ltbp 2/4S DKO胚胎的培养小鼠胚胎成纤维细胞（MEF）在无血清条件下形成了减少的微纤维网络，而通过添加重组LTBP-2或-4可以恢复微纤维形成。最后，LTBP-4在全身的异位表达恢复了Ltbp 2缺失小鼠眼中的睫状小带微纤维束。这些数据表明，LTBP-2和-4在体外和体内形成微纤维的稳健结构中具有关键的重叠功能。
Microfibrils are exracellular matrix components necessary for elastic fiber assembly and for suspending lenses. We previously reported that latent TGF-β binding protein 2 (LTBP-2), a microfibril-associated protein, is required for forming stable microfibril bundles in ciliary zonules. However, it was not understood why Ltbp2 null mice only showed an eye-specific phenotype, whereas LTBP-2 is abundantly expressed in other tissues containing microfibrils in wild type mice. Here, we show that LTBP-4, another microfibril-associated protein, compensates for the loss of LTBP-2 in microfibril formation. Ltbp2/4S double knockout (DKO) mice showed increased lethality due to emphysema, which was much more severe than that found in Ltbp4S null mice. Elastic fibers in the lungs of Ltbp2/4S DKO mice were severely disorganized and fragmented. Cultured mouse embryonic fibroblasts (MEFs) from Ltbp2/4S DKO embryos developed reduced microfibril meshwork in serum-free conditions, whereas the microfibril formation was restored by the addition of either recombinant LTBP-2 or -4. Finally, ectopic expression of LTBP-4 in the whole body restored ciliary zonule microfibril bundles in the eyes of Ltbp2 null mice. These data suggest that LTBP-2 and -4 have critical overlapping functions in forming the robust structure of microfibrils in vitro and in vivo.