The Role of Tissue Inhibitors of Metalloproteinases in Organ Development and Regulation of ADAMTS Family Metalloproteinases in Caenorhabditis elegans

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.