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

Abstract

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 MIG-17 and GON-1, 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), TIMP-1 and CRI-2. Analysis of the transcription and translation products for GFP/Venus fusions, with TIMP-1 or CRI-2, indicated that these inhibitors were secreted and localized to the basement membrane of gonads and the plasma membrane of germ cells. A timp-1 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 TIMP-1(C21S)::Venus mutant construct, in which the inhibitor coding sequence had been mutated. Moreover, genetic data suggested that TIMP-1 negatively regulates proteolysis of the a1 chain of type IV collagen. We also found that the loss-of-function observed for the mutants timp-1 and cri-2 involves a partial suppression of gonadal defects found for the mutants mig-17/ADAMTS and gon-1/ADAMTS, and that this suppression was canceled upon overexpression of gon-1 or mig-17, respectively. Based on these results, we propose that both TIMP-1 and CRI-2 act as inhibitors of MIG-17 and GON-1 ADAMTSs to regulate gonad development in a noncell-autonomous manner. KEYWORDS a disintegrin and metalloproteinase with thrombospondin motifs; tissue inhibitors of metalloproteinases; extracellular matrix; type IV collagen; gonad T HE extracellular matrix (ECM) supports cellular structure and function, and tissue integrity, by modulating the tissue-specific extracellular microenvironment during organ development and remodeling. Aberrant ECM remodeling leads to various pathological states including tissue degeneration, cancer progression, and tumor growth (

Ligand–Receptor Interactions Elucidate Sex-Specific Pathways in the Trajectory From Primordial Germ Cells to Gonia During Human Development

“…TIMP1 is an inhibitor of metalloproteinases that has been implicated in mammalian follicle maturation and ovulation (Chaffin and Stouffer, 1999;Stouffer et al, 2007;Stilley and Sharpe-Timms, 2012). Timp1 deficiency in mice results in reduced fertility (Nothnick, 2001) and in Caenorhabditis elegans reduces germ cell numbers and results in sterility (Kubota et al, 2019). Moreover, IGF/insulin signaling is an established driver of Sertoli cell proliferation and is required for normal testis development in mice (Nef et al, 2003;Pitetti et al, 2013a,b;Cannarella et al, 2017).…”

Extracellular Matrix: Emerging Roles and Potential Therapeutic Targets for Breast Cancer

“…Numerous evidence indicates that MMPs play important roles in tumor invasion, metastasis, and angiogenesis; these findings have led to the development and clinical application of MMP inhibitors (MPIs). The new generation of MPIs is more selective for pre-metastatic MMPs and is currently being developed and tested in preclinical cancer models (104)(105)(106)(107). In different models, tumor necrosis and apoptosis were induced by drug administration alone or in combination with chemotherapy.…”

Genes involved in chronic wound healing and their therapeutic potential

“…They act as inhibitors by binding to active MMPs, thereby controlling their proteolytic activity. 17 In chronic wounds, the balance between MMPs and TIMPs is disrupted, leading to excessive matrix degradation. Strategies that promote the expression or delivery of TIMPs may help restore this balance and regulate MMP activity.…”