Fu Liezhen, Ishizuya-Oka Atsuko, Buchholz Daniel R, Amano Tosikazu, Matsuda Hiroki, Shi Yun-Bo
Laboratory of Gene Regulation and Development, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 2005 Jul 29;280(30):27856-65. doi: 10.1074/jbc.M413275200. Epub 2005 Jun 1.
The matrix metalloproteinases are a family of proteases capable of degrading various components of the extracellular matrix. Expression studies have implicated the involvement of the matrix metalloproteinase stromelysin-3 (ST3) in tissue remodeling and pathogenesis. However, the in vivo role of ST3 has been difficult to study because of a lack of good animal models. Here we used intestinal remodeling during thyroid hormone-dependent metamorphosis of Xenopus laevis as a model to investigate in vivo the role of ST3 during postembryonic organ development in vertebrates. We generated transgenic tadpoles expressing ST3 under control of a heat shock-inducible promoter. We showed for the first time in vivo that wild type ST3 but not a catalytically inactive mutant was sufficient to induce larval epithelial cell death and fibroblast activation, events that normally occur only in the presence of thyroid hormone. We further demonstrated that these changes in cell fate are associated with altered gene expression in the intestine and remodeling of the intestinal basal lamina. These results thus suggest that ST3 regulates cell fate and tissue morphogenesis through direct or indirect ECM remodeling.
基质金属蛋白酶是一类能够降解细胞外基质各种成分的蛋白酶。表达研究表明基质金属蛋白酶基质溶素-3（ST3）参与组织重塑和发病机制。然而，由于缺乏良好的动物模型，ST3在体内的作用一直难以研究。在此，我们利用非洲爪蟾甲状腺激素依赖性变态过程中的肠道重塑作为模型，在体内研究ST3在脊椎动物胚胎后器官发育中的作用。我们构建了在热休克诱导型启动子控制下表达ST3的转基因蝌蚪。我们首次在体内表明，野生型ST3而非催化失活的突变体足以诱导幼虫上皮细胞死亡和成纤维细胞活化，而这些事件通常仅在甲状腺激素存在时才会发生。我们进一步证明，这些细胞命运的改变与肠道中基因表达的改变以及肠道基膜的重塑有关。因此，这些结果表明ST3通过直接或间接的细胞外基质重塑来调节细胞命运和组织形态发生。
