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      Mutations in fibulin-1 and collagen IV suppress the short healthspan of mig-17/ADAMTS mutants in Caenorhabditis elegans

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          Abstract

          The ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family metalloprotease MIG-17 plays a crucial role in the migration of gonadal distal tip cells (DTCs) in Caenorhabditis elegans. MIG-17 is secreted from the body wall muscle cells and localizes to the basement membranes (BMs) of various tissues including the gonadal BM where it regulates DTC migration through its catalytic activity. Missense mutations in the BM protein genes, let-2/ collagen IV a2 and fbl-1/fibulin-1, have been identified as suppressors of the gonadal defects observed in mig-17 mutants. Genetic analyses indicate that LET-2 and FBL-1 act downstream of MIG-17 to regulate DTC migration. In addition to the control of DTC migration, MIG-17 also plays a role in healthspan, but not in lifespan. Here, we examined whether let-2 and fbl-1 alleles can suppress the age-related phenotypes of mig-17 mutants. let-2(k196) fully and fbl-1(k201) partly, but not let-2(k193) and fbl-1(k206), suppressed the senescence defects of mig-17. Interestingly, fbl-1(k206), but not fbl-1(k201) or let-2 alleles, exhibited an extended lifespan compared to the wild type when combined with mig-17. These results reveal allele specific interactions between let-2 or fbl-1 and mig-17 in age-related phenotypes, indicating that basement membrane physiology plays an important role in organismal aging.

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          THE GENETICS OF CAENORHABDITIS ELEGANS

          Methods are described for the isolation, complementation and mapping of mutants of Caenorhabditis elegans, a small free-living nematode worm. About 300 EMS-induced mutants affecting behavior and morphology have been characterized and about one hundred genes have been defined. Mutations in 77 of these alter the movement of the animal. Estimates of the induced mutation frequency of both the visible mutants and X chromosome lethals suggests that, just as in Drosophila, the genetic units in C.elegans are large.
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            Stem cell competition orchestrates skin homeostasis and ageing

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              The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family

              The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase-dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysis
                Role: Formal analysis
                Role: ConceptualizationRole: Funding acquisitionRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLOS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                9 July 2024
                2024
                : 19
                : 7
                : e0305396
                Affiliations
                [001] Department of Bioscience, Kwansei Gakuin University, Sanda, Japan
                Baylor University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0009-0000-3913-4397
                Article
                PONE-D-24-09277
                10.1371/journal.pone.0305396
                11232982
                38980840
                868f732a-9321-4492-87cc-cff5ad8b4fff
                © 2024 Shibata et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 7 March 2024
                : 29 May 2024
                Page count
                Figures: 6, Tables: 1, Pages: 12
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001700, Ministry of Education, Culture, Sports, Science and Technology;
                Award ID: 22K20658
                Award Recipient :
                Funded by: Naito Grant for the advancement of natural science
                Award Recipient :
                Grant-in-Aid for Research Activity Start-up by the Ministry of Education, Culture, Sports, Science and Technology to YS(22K20658) and by the Naito Grant for the advancement of natural science to KN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Defecation
                Biology and Life Sciences
                Biochemistry
                Proteins
                Collagens
                Medicine and Health Sciences
                Epidemiology
                Medical Risk Factors
                Cancer Risk Factors
                Aging and Cancer
                Medicine and Health Sciences
                Oncology
                Cancer Risk Factors
                Aging and Cancer
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
                Model Organisms
                Caenorhabditis Elegans
                Research and Analysis Methods
                Model Organisms
                Caenorhabditis Elegans
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
                Animal Models
                Caenorhabditis Elegans
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Invertebrates
                Nematoda
                Caenorhabditis
                Caenorhabditis Elegans
                Biology and Life Sciences
                Zoology
                Animals
                Invertebrates
                Nematoda
                Caenorhabditis
                Caenorhabditis Elegans
                Biology and Life Sciences
                Genetics
                Phenotypes
                Biology and Life Sciences
                Developmental Biology
                Life Cycles
                Larvae
                Biology and Life Sciences
                Anatomy
                Reproductive System
                Genital Anatomy
                Gonads
                Medicine and Health Sciences
                Anatomy
                Reproductive System
                Genital Anatomy
                Gonads
                Medicine and Health Sciences
                Pediatrics
                Child Development
                Child Growth
                Growth Restriction
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                All relevant data are within the manuscript and its Supporting information files.

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