The Role of Tissue Inhibitors of Metalloproteinases in Organ Development and Regulation of ADAMTS Family Metalloproteinases in Caenorhabditis elegans
The Role of Tissue Inhibitors of Metalloproteinases in Organ Development and Regulation of ADAMTS Family Metalloproteinases in Caenorhabditis elegans
复制标题
DOI：
10.1534/genetics.119.301795
复制
发表时间：
2019-06-01
期刊：
影响因子：
3.3
通讯作者：
Sugimoto, Asako
中科院分区：
文献类型：
--
作者：
Kubota, Yukihiko;Nishiwaki, Kiyoji;Sugimoto, Asako
细胞外基质的重塑通过调节细胞形态和组织完整性来支持组织和器官的发育。然而，适当的细胞外基质重塑需要细胞外金属蛋白酶活性的时空调节。ADAMTS(一种带有血栓反应蛋白基序的去整合素和金属蛋白酶)家族的成员，包括和，是进化上保守的、分泌的、需要锌的金属蛋白酶。尽管这些蛋白是秀丽线虫性腺发生过程中细胞外基质重塑所必需的，但它们在体内的调节机制仍有待阐明。因此，我们重点研究了线虫组织金属蛋白酶抑制物(TIMPs)，以及。对GFP/Venus与或融合的转录和翻译产物的分析表明，这些抑制物分泌并定位于性腺基膜和生殖细胞的质膜。一个缺失突变体表现出性腺生长缺陷和不育，该突变体的表型可被TIMP-1：：Venus构建体完全挽救，但不能被(C21S)：：Venus突变体构建体拯救，其中抑制物编码序列已发生突变。此外，遗传数据表明，这对IV型胶原的α1链的蛋白分解具有负面调节作用。我们还发现，在突变体中观察到的功能丧失涉及到对突变体/ADAMTS和/ADAMTS发现的性腺缺陷的部分抑制，并且这种抑制分别在或的过度表达时被取消。基于这些结果，我们认为和都可以作为和ADAMTS的抑制剂，以非细胞自主的方式调节性腺发育。
Remodeling of the extracellular matrix supports tissue and organ development, by regulating cellular morphology and tissue integrity. However, proper extracellular matrix remodeling requires spatiotemporal regulation of extracellular metalloproteinase activity. Members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, including and , are evolutionarily conserved, secreted, zinc-requiring metalloproteinases. Although these proteases are required for extracellular matrix remodeling during gonadogenesis in Caenorhabditis elegans, their in vivo regulatory mechanisms remain to be delineated. Therefore, we focused on the C. elegans tissue inhibitors of metalloproteinases (TIMPs), and . Analysis of the transcription and translation products for GFP/Venus fusions, with or , indicated that these inhibitors were secreted and localized to the basement membrane of gonads and the plasma membrane of germ cells. A deletion mutant exhibited gonadal growth defects and sterility, and the phenotypes of this mutant were fully rescued by a TIMP-1::Venus construct, but not by a (C21S)::Venus mutant construct, in which the inhibitor coding sequence had been mutated. Moreover, genetic data suggested that negatively regulates proteolysis of the alpha 1 chain of type IV collagen. We also found that the loss-of-function observed for the mutants and involves a partial suppression of gonadal defects found for the mutants /ADAMTS and /ADAMTS, and that this suppression was canceled upon overexpression of or , respectively. Based on these results, we propose that both and act as inhibitors of and ADAMTSs to regulate gonad development in a noncell-autonomous manner.