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Juan Carlos Rodriguezmanzaneque - One of the best experts on this subject based on the ideXlab platform.
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extracellular protease ADAMTS1 is required at early stages of human uveal melanoma development by inducing stemness and endothelial like features on tumor cells
Cancers, 2020Co-Authors: Carlos Peristorres, Maria Del Carmen Plazacalonge, Raul Lopezdominguez, Silvia Dominguezgarcia, Antonio Barrientosduran, Pedro Carmonasaez, Juan Carlos RodriguezmanzanequeAbstract:Extracellular matrix remodeling within the tumor microenvironment has been recognized as a relevant dynamic framework during tumor growth. However, research on proteases that trigger this remodeling keeps revealing a wide range of actions including both pro- and anti-tumorigenic. The extracellular protease ADAMTS1 exemplifies this dual role. In this work, we first confirmed a positive correlation of ADAMTS1 with endothelial-like phenotype of human melanoma cells together with the finding of associated signatures, including key genes such as endothelial CDH5. Using a CRISPR-Cas9 approach, we observed that the inhibition of ADAMTS1 in an aggressive uveal melanoma model compromised its endothelial-like properties, and more importantly, caused a robust blockade on the progression of tumor xenografts. Although vasculature emerged affected in ADAMTS1-deficient tumors, the most relevant action implied the downregulation of endothelial CDH5 in tumor cells, in association with stemness markers. Indeed, melanoma sphere assays also revealed a deficient commitment to form spheres in the absence of ADAMTS1, directly correlating with stemness markers and, remarkably, also with CDH5. Finally, taking advantage of advanced bioinformatics tools and available public data of uveal melanomas, we disclosed new prognosis factors, including endothelial elements and ADAMTS proteases. Our findings support the key role of ADAMTS proteases for uveal melanoma development since earlier stages, modulating the complex crosstalk between extracellular matrix and the induction of stemness and endothelial-like features. To our knowledge, this is the first report that supports the development of therapeutic targets on the extracellular matrix to overcome uveal melanoma.
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inhibition of ADAMTS1 expression by lentiviral crispr cas9 gene editing technology
Methods of Molecular Biology, 2020Co-Authors: Carlos Peristorres, Maria Del Carmen Plazacalonge, Orlando Serrano, Juan Carlos RodriguezmanzanequeAbstract:The continuous improvement of gene editing tools has allowed a major revolution in biological sciences. Although a variety of gain and loss-of-function approaches have been widely used for the last decades, some limitations arose from non-specific targeting or lack of complete inhibition of the gene of interest. CRISPR/Cas9 editing technology introduced new and significant advantages because it can directly modify the gene of interest and completely blocks its expression.In the context of cancer studies, the heterogeneity of the tumor microenvironment requires comprehensive approaches to unveil the contribution of multiple genes. For example, a deeper understanding of the biology of proteases such as ADAMTS (a disintegrin and metalloproteinase with thrombospondin type 1 motifs) will improve our perspective of complex phenomena affected by extracellular matrix remodeling, including embryonic development, angiogenesis, immune infiltration, metastasis, and tumor plasticity. Here, we present a method using CRISPR/Cas9 technology to inhibit the expression of the representative ADAMTS1 in cancer cells. Following the first steps of gene edition, we pursue further selection of silenced cells and provide a detailed description of sequence analysis and validation assays. This method leads to inactivation of ADAMTS1 in cancer cells, providing a relevant biological tool that will allow subsequent in vivo and in vitro ADAMTS1 functional analysis.
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relevance of igfbp2 proteolysis in glioma and contribution of the extracellular protease ADAMTS1
Oncotarget, 2014Co-Authors: Estefania Martinoecharri, Maria Del Carmen Plazacalonge, Francesc Canals, Nuria Colome, Ruben Fernandezrodriguez, Joan Josep Bechserra, Noemi Vidal, Carmen Casal, Joan Seoane, Juan Carlos RodriguezmanzanequeAbstract:// Estefania Martino-Echarri 1 , Ruben Fernandez-Rodriguez 1 , Joan Josep Bech-Serra 2 , Maria del Carmen Plaza-Calonge 1 , Noemi Vidal 3 , Carmen Casal 1 , Nuria Colome 2 , Joan Seoane 2,4 , Francesc Canals 2 and Juan Carlos Rodriguez-Manzaneque 1 1 GENYO. Centre for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucia, Granada, Spain 2 Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Barcelona, Spain 3 Institut de Neuropatologia, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Spain 4 Institucio Catalana de Recerca I Estudis Avancats (ICREA), Barcelona, Spain Correspondence: J.C. Rodriguez-Manzaneque, email: // Keywords : ADAMTS, extracellular proteolysis, glioma, IGFBP2, proteomics Received : February 19, 2014 Accepted : May 24, 2014 Published : May 26, 2014 Abstract Expression of IGFBP2 ( Insulin-like Growth Factor Binding Protein 2 ) has been positively correlated with glioma progression. Although the proteolysis of IGFBP2 has been widely recognized, with consequences as a major modulator of IGFII signaling, the relevance of this post-translational modification has not been well studied in tumors. Using an in vivo proteomic approach by Isotope-Coded Protein Label (ICPL), we identified IGFBP2 as a target of the extracellular protease ADAMTS1 ( A Disintegrin And Metalloproteinase with ThromboSpondin motifs 1 ). Notably, the proteolytic pattern of IGFBP2 was also detected in human glioma culture cells and, more importantly, in all glioma samples evaluated. In addition, high expression of ADAMTS1 correlates with higher levels of cleaved IGFBP2 in glioblastoma multiforme cases. Using gene expression public databases, we confirmed that IGFBP2 is a poor prognosis marker for gliomas, and we also observed an important contribution of ADAMTS1.Finally, we showed the impact of ADAMTS1 on IGFII-mediated IGF1R phosphorylation and cellular migration. Our results support a functional interaction between IGFBP2 and ADAMTS1 and suggest the need to evaluate post-translational modifications of IGFBP2 in glioma, in order to approach new therapies.
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identification of substrates of the extracellular protease ADAMTS1 by dige proteomic analysis
Proteomics, 2006Co-Authors: Francesc Canals, Maria Del Carmen Plazacalonge, Nuria Colome, Cristina Ferrer, Juan Carlos RodriguezmanzanequeAbstract:Proteolytic modification of components of the extracellular milieu by metalloproteinases plays important roles in the regulation of multiple cellular and physiological processes and pathological conditions. ADAMTS1 is a secreted enzyme of the ADAMTS (adisintegrin and metalloproteinase with thrombospondin motifs) family of proteases, which is related to angiogenesis and inflammation processes. Here, we describe a proteomic screening for putative ADAMTS1 substrates by analyzing the protein profiles obtained from cultures of transfected cells overexpressing the protease as compared to parental cells. Conditioned medium proteins of cultures of the two cell lines have been quantitatively compared by DIGE. Proteins showing differential levels have been identified by MS techniques leading to the finding of five potential new substrates of ADAMTS1: the basement membrane proteins nidogen-1 and -2, the desmosomal protein desmocollin-3, and the extracellular glycoproteins dystroglycan 1 and Mac-2-binding protein. Nidogen-1 and -2 have been further validated as substrates by immunochemical analysis. Our results demonstrate the utility of the DIGE proteomic technique for the discovery of specific substrates of matrix proteases.
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ADAMTS1 cleaves aggrecan at multiple sites and is differentially inhibited by metalloproteinase inhibitors
Biochemical and Biophysical Research Communications, 2002Co-Authors: Juan Carlos Rodriguezmanzaneque, John D. Sandy, Jennifer Westling, Shelley N M Thai, Alfonso Luque, Vera Knauper, Gillian Murphy, Luisa M IruelaarispeAbstract:ADAMTS1 is a secreted protein that belongs to the recently described ADAMTS (a disintegrin and metalloprotease with thrombospondin repeats) family of proteases. Evaluation of ADAMTS1 catalytic activity on a panel of extracellular matrix proteins showed a restrictive substrate specificity which includes some proteoglycans. Our results demonstrated that human ADAMTS1 cleaves aggrecan at a previously shown site by its mouse homolog, but we have also identified additional cleavage sites that ultimately confirm the classification of this protease as an 'aggrecanase'. Specificity of ADAMTS1 activity was further verified when a point mutation in the zinc-binding domain abolished its catalytic effects, and latency conferred by the prodomain was also demonstrated using a furin cleavage site mutant. Suppression of ADAMTS1 activity was accomplished with a specific monoclonal antibody and some metalloprotease inhibitors, including tissue inhibitor of metalloproteinases 2 and 3. Finally, we developed an activity assay using an artificial peptide substrate based on the interglobular domain cleavage site (E(373)-A) of rat aggrecan.
Derek Boerboom - One of the best experts on this subject based on the ideXlab platform.
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partially redundant functions of ADAMTS1 and adamts4 in the perinatal development of the renal medulla
Developmental Dynamics, 2011Co-Authors: Derek Boerboom, Jeanfrancois Lafond, Xiaofeng Zheng, Evelyne Lapointe, Laureane Mittaz, Alexandre Boyer, Melanie April Pritchard, Francesco J Demayo, John S MortAbstract:Adamts4 encodes a widely-expressed proteinase thought to be involved in processes ranging from cartilage metabolism to ovarian follicle development. To study its physiological roles, Adamts4-null mice were created by gene targeting. Unexpectedly, these were found to be phenotypically normal, suggesting that other gene(s) may compensate for its loss. Adamts4−/− mice were, therefore, crossed with a strain lacking ADAMTS1, whose pattern of expression and substrate specificity overlap that of Adamts4. Most (>95%) ADAMTS1−/−;Adamts4−/− mice died within 72 hr after birth with a marked thinning of the renal medulla. The renal defect was not observed in embryonic ADAMTS1−/−;Adamts4−/− kidneys, but became apparent around birth. The few (<5%) ADAMTS1−/−;Adamts4−/− animals to reach adulthood had the same renal phenotype seen in newborns. This study is thus the first to report Adamts4 expression and function in the mammalian kidney, and to demonstrate that ADAMTS1 and Adamts4 play redundant and essential roles in perinatal kidney development. Developmental Dynamics 240:1806–1814, 2011. © 2011 Wiley-Liss, Inc.
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partially redundant functions of ADAMTS1 and adamts4 in the perinatal development of the renal medulla
Developmental Dynamics, 2011Co-Authors: Derek Boerboom, Jeanfrancois Lafond, Xiaofeng Zheng, Evelyne Lapointe, Laureane Mittaz, Alexandre Boyer, Melanie April Pritchard, Francesco J Demayo, John S MortAbstract:Adamts4 encodes a widely-expressed proteinase thought to be involved in processes ranging from cartilage metabolism to ovarian follicle development. To study its physiological roles, Adamts4-null mice were created by gene targeting. Unexpectedly, these were found to be phenotypically normal, suggesting that other gene(s) may compensate for its loss. Adamts4(-/-) mice were, therefore, crossed with a strain lacking ADAMTS1, whose pattern of expression and substrate specificity overlap that of Adamts4. Most (>95%) ADAMTS1(-/-) ;Adamts4(-/-) mice died within 72 hr after birth with a marked thinning of the renal medulla. The renal defect was not observed in embryonic ADAMTS1(-/-) ;Adamts4(-/-) kidneys, but became apparent around birth. The few (<5%) ADAMTS1(-/-) ;Adamts4(-/-) animals to reach adulthood had the same renal phenotype seen in newborns. This study is thus the first to report Adamts4 expression and function in the mammalian kidney, and to demonstrate that ADAMTS1 and Adamts4 play redundant and essential roles in perinatal kidney development.
Suneel S. Apte - One of the best experts on this subject based on the ideXlab platform.
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a disintegrin like and metalloproteinase domain with thrombospondin type 1 motif 9 adamts9 regulates fibronectin fibrillogenesis and turnover
Journal of Biological Chemistry, 2019Co-Authors: Lauren W Wang, Sumeda Nandadasa, Douglas S Annis, Johanne Dubail, Deane F Mosher, Belinda Willard, Suneel S. ApteAbstract:The secreted metalloprotease ADAMTS9 has dual roles in extracellular matrix (ECM) turnover and biogenesis of the primary cilium during mouse embryogenesis. Its gene locus is associated with several human traits and disorders, but ADAMTS9 has few known interacting partners or confirmed substrates. Here, using a yeast two-hybrid screen for proteins interacting with its C-terminal Gon1 domain, we identified three putative ADAMTS9-binding regions in the ECM glycoprotein fibronectin. Using solid-phase binding assays and surface plasmon resonance experiments with purified proteins, we demonstrate that ADAMTS9 and fibronectin interact. ADAMTS9 constructs, including those lacking Gon1, co-localized with fibronectin fibrils formed by cultured fibroblasts lacking fibrillin-1, which co-localizes with fibronectin and binds several ADAMTSs. We observed no fibrillar ADAMTS9 staining after blockade of fibroblast fibronectin fibrillogenesis with a peptide based on the functional upstream domain of a Staphylococcus aureus adhesin. These findings indicate that ADAMTS9 binds fibronectin dimers and fibrils directly through multiple sites in both molecules. Proteolytically active ADAMTS9, but not a catalytically inactive variant, disrupted fibronectin fibril networks formed by fibroblasts in vitro, and ADAMTS9-deficient RPE1 cells assembled a robust fibronectin fibril network, unlike WT cells. Targeted LC-MS analysis of fibronectin digested by ADAMTS9-expressing cells identified a semitryptic peptide arising from cleavage at Gly2196-Leu2197 We noted that this scissile bond is in the linker between fibronectin modules III17 and I10, a region targeted also by other proteases. These findings, along with stronger fibronectin staining previously observed in Adamts9 mutant embryos, suggest that ADAMTS9 contributes to fibronectin turnover during ECM remodeling.
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adamtsl4 a secreted glycoprotein widely distributed in the eye binds fibrillin 1 microfibrils and accelerates microfibril biogenesis
Investigative Ophthalmology & Visual Science, 2012Co-Authors: Luis Alexandre Rassi Gabriel, Lauren W Wang, Hannah L Bader, Jason C Ho, Alana K Majors, Joe G Hollyfield, Elias I Traboulsi, Suneel S. ApteAbstract:The suspensory ligament of the lens (zonule of Zinn) centers the ocular lens in the path of light and transmits ciliary muscle forces involved in accommodation. The zonule is a circular cell-free structure that is composed of radially oriented cablelike microfibrils. It extends from the ciliary body to the equatorial region of the lens capsule. Zonule microfibrils are composed primarily of the matrix glycoprotein fibrillin-1.1–4 Fibrillin-1 is also a major component of tissue microfibrils, which are especially abundant in association with elastic fibers in skin, arteries, and lung.3,5 Ectopia lentis, which refers to subluxation of the lens from its centered position, may result from trauma to the zonule or may be caused by dysgenesis or fragility of the zonule as a consequence of inherited disorders. For example, dominantly inherited FBN1 mutations cause Marfan syndrome (MFS), in which ectopia lentis is a major clinical manifestation.6 Less commonly, dominantly inherited FBN1 mutations cause dominantly inherited isolated ectopia lentis (MIM129600), i.e., without other clinical connective tissue manifestations of MFS.7,8 Recently, ADAMTSL4 mutations were identified in both recessively inherited isolated ectopia lentis9–12 and ectopia lentis et pupillae.13 Ectopia lentis has also been described in Weill-Marchesani syndrome (MIM277600; MIM608328),14 which is caused by either ADAMTS1015 or FBN1 mutations,16 inherited in a recessive or dominant fashion, respectively. ADAMTS17 mutations were identified in a WMS-like syndrome in which ectopia lentis was also present.17 These genetic findings suggest that at least three members of the ADAMTS superfamily of secreted proteins are involved in the normal formation, maintenance, or both of the zonule and the abnormalities therein in case of defects in these proteins. Recently, ADAMTSL6, which of all family members is the most similar to ADAMTSL4, was shown to bind directly to fibrillin-1 and to enhance its assembly both in tissue culture and in transgenic mice overexpressing it.18 Similarly, binding of ADAMTS10 to fibrillin-1 and to fibrillin microfibrils was identified recently, and ADAMTS10 was shown to enhance microfibril biogenesis in vitro.19 Collectively, these findings led to the hypothesis that ADAMTSL4 functions to promote fibrillin-1 assembly in the genesis, maintenance, or both of the zonular apparatus. The ADAMTS superfamily comprises 19 ADAMTS proteases and seven ADAMTS-like proteins.20 ADAMTS proteases consist of two distinct domains, namely, a zinc-binding metalloprotease domain and an ancillary domain containing one or more thrombospondin type 1 repeats. In contrast, ADAMTS-like proteins have a modular structure related to the ADAMTS ancillary domain and lack the protease domain.20 Hence, they are not enzymes but are secreted glycoproteins deposited into the ECM. Because little is known about ADAMTSL4, we determined ADAMTSL4 distribution in the eye and investigated its potential function vis-a-vis fibrillin-1. Our results suggest that ADAMTSL4 is a widely distributed glycoprotein that associates with fibrillin-1 and may accelerate fibrillin-1 assembly.
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cooperation of two adamts metalloproteases in closure of the mouse palate identifies a requirement for versican proteolysis in regulating palatal mesenchyme proliferation
Development, 2010Co-Authors: Hiroyuki Enomoto, Robert P.t. Somerville, Courtney M Nelson, Katrina Mielke, Laura J Dixon, Kimerly A Powell, Suneel S. ApteAbstract:We have identified a role for two evolutionarily related, secreted metalloproteases of the ADAMTS family, ADAMTS20 and ADAMTS9, in palatogenesis. Adamts20 mutations cause the mouse white-spotting mutant belted (bt), whereas Adamts9 is essential for survival beyond 7.5 days gestation (E7.5). Functional overlap of Adamts9 with Adamts20 was identified using Adamts9+/–;bt/bt mice, which have a fully penetrant cleft palate. Palate closure was delayed, although eventually completed, in both Adamts9+/–;bt/+ and bt/bt mice, demonstrating cooperation of these genes. Adamts20 is expressed in palatal mesenchyme, whereas Adamts9 is expressed exclusively in palate microvascular endothelium. Palatal shelves isolated from Adamts9+/–;bt/bt mice fused in culture, suggesting an intact epithelial TGFβ3 signaling pathway. Cleft palate resulted from a temporally specific delay in palatal shelf elevation and growth towards the midline. Mesenchyme of Adamts9+/–;bt/bt palatal shelves had reduced cell proliferation, a lower cell density and decreased processing of versican (VCAN), an extracellular matrix (ECM) proteoglycan and ADAMTS9/20 substrate, from E13.5 to E14.5. Vcan haploinsufficiency led to greater penetrance of cleft palate in bt mice, with a similar defect in palatal shelf extension as Adamts9+/–;bt/bt mice. Cell density was normal in bt/bt;Vcanhdf/+ mice, consistent with reduced total intact versican in ECM, but impaired proliferation persisted in palate mesenchyme, suggesting that ADAMTS-cleaved versican is required for cell proliferation. These findings support a model in which cooperative versican proteolysis by ADAMTS9 in vascular endothelium and by ADAMTS20 in palate mesenchyme drives palatal shelf sculpting and extension.
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discovery and characterization of a novel widely expressed metalloprotease ADAMTS10 and its proteolytic activation
Journal of Biological Chemistry, 2004Co-Authors: Robert P.t. Somerville, Katherine A Jungers, Suneel S. ApteAbstract:Abstract We describe the discovery and characterization of ADAMTS10, a novel metalloprotease encoded by a locus on human chromosome 19 and mouse chromosome 17. ADAMTS10 has the typical modular organization of the ADAMTS family, with five thrombospondin type 1 repeats and a cysteine-rich PLAC (protease and lacunin) domain at the carboxyl terminus. Its domain organization and primary structure is similar to a novel long form of ADAMTS6. In contrast to many ADAMTS proteases, ADAMTS10 is widely expressed in adult tissues and throughout mouse embryo development. In situ hybridization analysis showed widespread expression of ADAMTS10 in the mouse embryo until 12.5 days of gestation, after which it is then expressed in a more restricted fashion, with especially strong expression in developing lung, bone, and craniofacial region. Mesenchymal, not epithelial, expression in the developing lung, kidney, gonad, salivary gland, and gastrointestinal tract is a consistent feature of ADAMTS10 regulation. N-terminal sequencing and treatment with decanoyl-Arg-Val-Lys-Arg-chloromethylketone indicate that the ADAMTS10 zymogen is processed by a subtilisin-like proprotein convertase at two sites (Arg64↓Gly and Arg233↓Ser). The widespread expression of ADAMTS10 suggests that furin, a ubiquitously expressed proprotein convertase, is the likely processing enzyme. ADAMTS10 expressed in HEK293F and COS-1 cells is N-glycosylated and is secreted into the medium, as well as sequestered at the cell surface and extracellular matrix, as demonstrated by cell surface biotinylation and immunolocalization in nonpermeabilized cells. ADAMTS10 is a functional metalloprotease as demonstrated by cleavage of α2-macroglobulin, although physiological substrates are presently unknown.
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adamts7b the full length product of the adamts7 gene is a chondroitin sulfate proteoglycan containing a mucin domain
Journal of Biological Chemistry, 2004Co-Authors: Robert P.t. Somerville, Jean Michel Longpre, Elizabeth D Apel, Renate M Lewis, Lauren W Wang, Joshua R Sanes, Richard D Leduc, Suneel S. ApteAbstract:Abstract We have characterized ADAMTS7B, the authentic full-length protein product of the ADAMTS7 gene. ADAMTS7B has a domain organization similar to that of ADAMTS12, with a total of eight thrombospondin type 1 repeats in its ancillary domain. Of these, seven are arranged in two distinct clusters that are separated by a mucin domain. Unique to the ADAMTS family, ADAMTS7B is modified by attachment of the glycosaminoglycan chondroitin sulfate within the mucin domain, thus rendering it a proteoglycan. Glycosaminoglycan addition has potentially important implications for ADAMTS7B cellular localization and for substrate recognition. Although not an integral membrane protein, ADAMTS7B is retained near the cell surface of HEK293F cells via interactions involving both the ancillary domain and the prodomain. ADAMTS7B undergoes removal of the prodomain by a multistep furin-dependent mechanism. At least part of the final processing event, i.e. cleavage following Arg220 (mouse sequence annotation), occurs at the cell surface. ADAMTS7B is an active metalloproteinase as shown by its ability to cleave α2-macroglobulin, but it does not cleave specific peptide bonds in versican and aggrecan attacked by ADAMTS proteases. Together with ADAMTS12, whose primary structure also predicts a mucin domain, ADAMTS7B constitutes a unique subgroup of the ADAMTS family.
John S Mort - One of the best experts on this subject based on the ideXlab platform.
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partially redundant functions of ADAMTS1 and adamts4 in the perinatal development of the renal medulla
Developmental Dynamics, 2011Co-Authors: Derek Boerboom, Jeanfrancois Lafond, Xiaofeng Zheng, Evelyne Lapointe, Laureane Mittaz, Alexandre Boyer, Melanie April Pritchard, Francesco J Demayo, John S MortAbstract:Adamts4 encodes a widely-expressed proteinase thought to be involved in processes ranging from cartilage metabolism to ovarian follicle development. To study its physiological roles, Adamts4-null mice were created by gene targeting. Unexpectedly, these were found to be phenotypically normal, suggesting that other gene(s) may compensate for its loss. Adamts4−/− mice were, therefore, crossed with a strain lacking ADAMTS1, whose pattern of expression and substrate specificity overlap that of Adamts4. Most (>95%) ADAMTS1−/−;Adamts4−/− mice died within 72 hr after birth with a marked thinning of the renal medulla. The renal defect was not observed in embryonic ADAMTS1−/−;Adamts4−/− kidneys, but became apparent around birth. The few (<5%) ADAMTS1−/−;Adamts4−/− animals to reach adulthood had the same renal phenotype seen in newborns. This study is thus the first to report Adamts4 expression and function in the mammalian kidney, and to demonstrate that ADAMTS1 and Adamts4 play redundant and essential roles in perinatal kidney development. Developmental Dynamics 240:1806–1814, 2011. © 2011 Wiley-Liss, Inc.
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partially redundant functions of ADAMTS1 and adamts4 in the perinatal development of the renal medulla
Developmental Dynamics, 2011Co-Authors: Derek Boerboom, Jeanfrancois Lafond, Xiaofeng Zheng, Evelyne Lapointe, Laureane Mittaz, Alexandre Boyer, Melanie April Pritchard, Francesco J Demayo, John S MortAbstract:Adamts4 encodes a widely-expressed proteinase thought to be involved in processes ranging from cartilage metabolism to ovarian follicle development. To study its physiological roles, Adamts4-null mice were created by gene targeting. Unexpectedly, these were found to be phenotypically normal, suggesting that other gene(s) may compensate for its loss. Adamts4(-/-) mice were, therefore, crossed with a strain lacking ADAMTS1, whose pattern of expression and substrate specificity overlap that of Adamts4. Most (>95%) ADAMTS1(-/-) ;Adamts4(-/-) mice died within 72 hr after birth with a marked thinning of the renal medulla. The renal defect was not observed in embryonic ADAMTS1(-/-) ;Adamts4(-/-) kidneys, but became apparent around birth. The few (<5%) ADAMTS1(-/-) ;Adamts4(-/-) animals to reach adulthood had the same renal phenotype seen in newborns. This study is thus the first to report Adamts4 expression and function in the mammalian kidney, and to demonstrate that ADAMTS1 and Adamts4 play redundant and essential roles in perinatal kidney development.
Paul E. Gottschall - One of the best experts on this subject based on the ideXlab platform.
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Selective Decline of Synaptic Protein Levels in the Frontal Cortex of Female Mice Deficient in the
2016Co-Authors: Extracellular Metalloproteinase Adamts, Matthew D. Howell, Antoni X. Torres-collado, Luisa M. Iruela-arispe, Paul E. GottschallAbstract:The chondroitin sulfate-bearing proteoglycans, also known as lecticans, are a major component of the extracellular matrix (ECM) in the central nervous system and regulate neural plasticity. Growing evidence indicates that endogenous, extracellular metalloproteinases that cleave lecticans mediate neural plasticity by altering the structure of ECM aggregates. The bulk of this in vivo data examined the matrix metalloproteinases, but another metalloproteinase family that cleaves lecticans, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), modulates structural plasticity in vitro, although few in vivo studies have tested this concept. Thus, the purpose of this study was to examine the neurological phenotype of a mouse deficient in ADAMTS1. ADAMTS1 mRNA was absent in the ADAMTS1 null mouse frontal cortex, but there was no change in the abundance or proteolytic processing of the prominent lecticans brevican and versican V2. However, there was a marked increase in the perinatal lectican neurocan in juvenile ADAMTS1 null female frontal cortex. More prominently, there were declines in synaptic protein levels in the ADAMTS1 null female, but not male, frontal cortex beginning at postnatal day 28. These synaptic marker declines did not affect learning or memory in the adult female ADAMTS1 null mice when tested with the radial-arm water maze. These results indicate that in vivo ADAMTS1 knockout leads to sexual dimorphism in frontal cortex synaptic protein levels. Since changes in lectican abundance and proteolytic processing did not accompany the synaptic protein declines, ADAMTS1 may play a nonproteolytic role in regulating neura
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adamts expression and function in central nervous system injury and disorders
Matrix Biology, 2015Co-Authors: Paul E. Gottschall, Matthew D. HowellAbstract:The components of the adult extracellular matrix in the central nervous system form a lattice-like structure that is deposited as perineuronal nets, around axon initial segments and as synapse-associated matrix. An abundant component of this matrix is the lecticans, chondroitin sulfate-bearing proteoglycans that are the major substrate for several members of the ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) family. Since lecticans are key regulators of neural plasticity, ADAMTS cleavage of lecticans would likely also contribute to neuroplasticity. Indeed, many studies have examined the neuroplastic contribution of the ADAMTSs to damage and recovery after injury and in central nervous system disease. Much of this data supports a role for the ADAMTSs in recovery and repair following spinal cord injury by stimulating axonal outgrowth after degradation of a glial scar and improving synaptic plasticity following seizure-induced neural damage in the brain. The action of the ADAMTSs in chronic diseases of the central nervous system appears to be more complex and less well-defined. Increasing evidence indicates that lecticans participate in synaptic plasticity in neurodegenerative disease states. It will be interesting to examine how ADAMTS expression and action would affect the progression of these diseases.
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selective decline of synaptic protein levels in the frontal cortex of female mice deficient in the extracellular metalloproteinase ADAMTS1
PLOS ONE, 2012Co-Authors: Matthew D. Howell, Luisa M Iruelaarispe, Antoni X Torrescollado, Paul E. GottschallAbstract:The chondroitin sulfate-bearing proteoglycans, also known as lecticans, are a major component of the extracellular matrix (ECM) in the central nervous system and regulate neural plasticity. Growing evidence indicates that endogenous, extracellular metalloproteinases that cleave lecticans mediate neural plasticity by altering the structure of ECM aggregates. The bulk of this in vivo data examined the matrix metalloproteinases, but another metalloproteinase family that cleaves lecticans, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), modulates structural plasticity in vitro, although few in vivo studies have tested this concept. Thus, the purpose of this study was to examine the neurological phenotype of a mouse deficient in ADAMTS1. ADAMTS1 mRNA was absent in the ADAMTS1 null mouse frontal cortex, but there was no change in the abundance or proteolytic processing of the prominent lecticans brevican and versican V2. However, there was a marked increase in the perinatal lectican neurocan in juvenile ADAMTS1 null female frontal cortex. More prominently, there were declines in synaptic protein levels in the ADAMTS1 null female, but not male, frontal cortex beginning at postnatal day 28. These synaptic marker declines did not affect learning or memory in the adult female ADAMTS1 null mice when tested with the radial-arm water maze. These results indicate that in vivo ADAMTS1 knockout leads to sexual dimorphism in frontal cortex synaptic protein levels. Since changes in lectican abundance and proteolytic processing did not accompany the synaptic protein declines, ADAMTS1 may play a nonproteolytic role in regulating neural plasticity.