ADAMTS Metalloproteases Generate Active Versican Fragments that Regulate Interdigital Web Regression
We show that combinatorial mouse alleles for the secreted metalloproteases Adamts5, Adamts20 ( bt), and Adamts9 result in fully penetrant soft-tissue syndactyly. Interdigital webs in Adamts5 −/−;bt/bt mice had reduced apoptosis and decreased cleavage of the proteoglycan versican; however, the BMP-FG...
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| Published in | Developmental cell Vol. 17; no. 5; pp. 687 - 698 |
|---|---|
| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Cambridge, MA
Elsevier Inc
17.11.2009
Cell Press |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1534-5807 1878-1551 1878-1551 |
| DOI | 10.1016/j.devcel.2009.09.008 |
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| Abstract | We show that combinatorial mouse alleles for the secreted metalloproteases
Adamts5,
Adamts20 (
bt), and
Adamts9 result in fully penetrant soft-tissue syndactyly. Interdigital webs in
Adamts5
−/−;bt/bt
mice had reduced apoptosis and decreased cleavage of the proteoglycan versican; however, the BMP-FGF axis, which regulates interdigital apoptosis was unaffected. BMP4 induced apoptosis, but without concomitant versican proteolysis. Haploinsufficiency of either
Vcan or
Fbln1, a cofactor for versican processing by ADAMTS5, led to highly penetrant syndactyly in
bt mice, suggesting that cleaved versican was essential for web regression. The local application of an aminoterminal versican fragment corresponding to ADAMTS-processed versican, induced cell death in
Adamts5
−/−;bt/bt
webs. Thus, ADAMTS proteases cooperatively maintain versican proteolysis above a required threshold to create a permissive environment for apoptosis. The data highlight the developmental significance of proteolytic action on the ECM, not only as a clearance mechanism, but also as a means to generate bioactive versican fragments. |
|---|---|
| AbstractList | We show that combinatorial mouse alleles for the secreted metalloproteases
Adamts5
,
Adamts20
(
bt
), and
Adamts9
result in fully penetrant soft-tissue syndactyly. Interdigital webs in
Adamts5
−/−
; bt/bt
mice had reduced apoptosis and decreased cleavage of the proteoglycan versican; however, the BMP-FGF axis, which regulates interdigital apoptosis was unaffected. BMP4 induced apoptosis, but without concomitant versican proteolysis. Haploinsufficiency of either
Vcan
or
Fbln1
, a co-factor for versican processing by ADAMTS5, led to highly penetrant syndactyly in
bt
mice, suggesting that cleaved versican was essential for web regression. The local application of an amino-terminal versican fragment corresponding to ADAMTS-processed versican, induced cell death in
Adamts5
−/−
; bt/bt
webs. Thus, ADAMTS proteases cooperatively maintain versican proteolysis above a required threshold to create a permissive environment for apoptosis. The data highlight the developmental significance of proteolytic action on the ECM, not only as a clearance mechanism, but also as a means to generate bioactive versican fragments. We show that combinatorial mouse alleles for the secreted metalloproteases Adamts5, Adamts20 ( bt), and Adamts9 result in fully penetrant soft-tissue syndactyly. Interdigital webs in Adamts5 −/−;bt/bt mice had reduced apoptosis and decreased cleavage of the proteoglycan versican; however, the BMP-FGF axis, which regulates interdigital apoptosis was unaffected. BMP4 induced apoptosis, but without concomitant versican proteolysis. Haploinsufficiency of either Vcan or Fbln1, a cofactor for versican processing by ADAMTS5, led to highly penetrant syndactyly in bt mice, suggesting that cleaved versican was essential for web regression. The local application of an aminoterminal versican fragment corresponding to ADAMTS-processed versican, induced cell death in Adamts5 −/−;bt/bt webs. Thus, ADAMTS proteases cooperatively maintain versican proteolysis above a required threshold to create a permissive environment for apoptosis. The data highlight the developmental significance of proteolytic action on the ECM, not only as a clearance mechanism, but also as a means to generate bioactive versican fragments. We show that combinatorial mouse alleles for the secreted metalloproteases Adamts5, Adamts20 (bt), and Adamts9 result in fully penetrant soft-tissue syndactyly. Interdigital webs in Adamts5(-/-);bt/bt mice had reduced apoptosis and decreased cleavage of the proteoglycan versican; however, the BMP-FGF axis, which regulates interdigital apoptosis was unaffected. BMP4 induced apoptosis, but without concomitant versican proteolysis. Haploinsufficiency of either Vcan or Fbln1, a cofactor for versican processing by ADAMTS5, led to highly penetrant syndactyly in bt mice, suggesting that cleaved versican was essential for web regression. The local application of an aminoterminal versican fragment corresponding to ADAMTS-processed versican, induced cell death in Adamts5(-/-);bt/bt webs. Thus, ADAMTS proteases cooperatively maintain versican proteolysis above a required threshold to create a permissive environment for apoptosis. The data highlight the developmental significance of proteolytic action on the ECM, not only as a clearance mechanism, but also as a means to generate bioactive versican fragments.We show that combinatorial mouse alleles for the secreted metalloproteases Adamts5, Adamts20 (bt), and Adamts9 result in fully penetrant soft-tissue syndactyly. Interdigital webs in Adamts5(-/-);bt/bt mice had reduced apoptosis and decreased cleavage of the proteoglycan versican; however, the BMP-FGF axis, which regulates interdigital apoptosis was unaffected. BMP4 induced apoptosis, but without concomitant versican proteolysis. Haploinsufficiency of either Vcan or Fbln1, a cofactor for versican processing by ADAMTS5, led to highly penetrant syndactyly in bt mice, suggesting that cleaved versican was essential for web regression. The local application of an aminoterminal versican fragment corresponding to ADAMTS-processed versican, induced cell death in Adamts5(-/-);bt/bt webs. Thus, ADAMTS proteases cooperatively maintain versican proteolysis above a required threshold to create a permissive environment for apoptosis. The data highlight the developmental significance of proteolytic action on the ECM, not only as a clearance mechanism, but also as a means to generate bioactive versican fragments. We show that combinatorial mouse alleles for the secreted metalloproteases Adamts5, Adamts20 (bt), and Adamts9 result in fully penetrant soft-tissue syndactyly. Interdigital webs in Adamts5(-/-);bt/bt mice had reduced apoptosis and decreased cleavage of the proteoglycan versican; however, the BMP-FGF axis, which regulates interdigital apoptosis was unaffected. BMP4 induced apoptosis, but without concomitant versican proteolysis. Haploinsufficiency of either Vcan or Fbln1, a cofactor for versican processing by ADAMTS5, led to highly penetrant syndactyly in bt mice, suggesting that cleaved versican was essential for web regression. The local application of an aminoterminal versican fragment corresponding to ADAMTS-processed versican, induced cell death in Adamts5(-/-);bt/bt webs. Thus, ADAMTS proteases cooperatively maintain versican proteolysis above a required threshold to create a permissive environment for apoptosis. The data highlight the developmental significance of proteolytic action on the ECM, not only as a clearance mechanism, but also as a means to generate bioactive versican fragments. |
| Author | Lindner, Volkhard Sasaki, Takako Cooley, Marion A. Apte, Suneel S. McCulloch, Daniel R. Dixon, Laura J. Wylie, James D. Nelson, Courtney M. Argraves, W. Scott Silver, Debra L. |
| AuthorAffiliation | 4 Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 5 Department of Anatomy and Cell Biology, Medical University of South Carolina, Charleston, SC 1 Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH 2 Genetic Disease Research Branch, National Human Genome Research Institute, Bethesda, MD, USA 3 Maine Medical Center Research Institute, Scarborough, ME |
| AuthorAffiliation_xml | – name: 4 Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR – name: 5 Department of Anatomy and Cell Biology, Medical University of South Carolina, Charleston, SC – name: 1 Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH – name: 3 Maine Medical Center Research Institute, Scarborough, ME – name: 2 Genetic Disease Research Branch, National Human Genome Research Institute, Bethesda, MD, USA |
| Author_xml | – sequence: 1 givenname: Daniel R. surname: McCulloch fullname: McCulloch, Daniel R. organization: Department of Biomedical Engineering, Lerner Research Institute, ND20-Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA – sequence: 2 givenname: Courtney M. surname: Nelson fullname: Nelson, Courtney M. organization: Department of Biomedical Engineering, Lerner Research Institute, ND20-Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA – sequence: 3 givenname: Laura J. surname: Dixon fullname: Dixon, Laura J. organization: Department of Biomedical Engineering, Lerner Research Institute, ND20-Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA – sequence: 4 givenname: Debra L. surname: Silver fullname: Silver, Debra L. organization: Genetic Disease Research Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA – sequence: 5 givenname: James D. surname: Wylie fullname: Wylie, James D. organization: Department of Biomedical Engineering, Lerner Research Institute, ND20-Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA – sequence: 6 givenname: Volkhard surname: Lindner fullname: Lindner, Volkhard organization: Maine Medical Center Research Institute, Scarborough, ME 04074, USA – sequence: 7 givenname: Takako surname: Sasaki fullname: Sasaki, Takako organization: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 97239, USA – sequence: 8 givenname: Marion A. surname: Cooley fullname: Cooley, Marion A. organization: Department of Anatomy and Cell Biology, Medical University of South Carolina, Charleston, SC 29403, USA – sequence: 9 givenname: W. Scott surname: Argraves fullname: Argraves, W. Scott organization: Department of Anatomy and Cell Biology, Medical University of South Carolina, Charleston, SC 29403, USA – sequence: 10 givenname: Suneel S. surname: Apte fullname: Apte, Suneel S. email: aptes@ccf.org organization: Department of Biomedical Engineering, Lerner Research Institute, ND20-Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22174766$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/19922873$$D View this record in MEDLINE/PubMed |
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| IngestDate | Thu Aug 21 13:40:42 EDT 2025 Fri Jul 11 11:28:21 EDT 2025 Mon Jul 21 06:01:09 EDT 2025 Mon Jul 21 09:14:12 EDT 2025 Thu Apr 24 23:03:06 EDT 2025 Tue Jul 01 02:37:30 EDT 2025 Fri Feb 23 02:26:43 EST 2024 |
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| Issue | 5 |
| Keywords | CELLCYCLE DEVBIO SIGNALING Development Regression Regulation(control) |
| Language | English |
| License | http://www.elsevier.com/open-access/userlicense/1.0 CC BY 4.0 |
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| PublicationDate | 2009-11-17 |
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| PublicationPlace | Cambridge, MA |
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| PublicationTitle | Developmental cell |
| PublicationTitleAlternate | Dev Cell |
| PublicationYear | 2009 |
| Publisher | Elsevier Inc Cell Press |
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| Snippet | We show that combinatorial mouse alleles for the secreted metalloproteases
Adamts5,
Adamts20 (
bt), and
Adamts9 result in fully penetrant soft-tissue... We show that combinatorial mouse alleles for the secreted metalloproteases Adamts5, Adamts20 (bt), and Adamts9 result in fully penetrant soft-tissue... We show that combinatorial mouse alleles for the secreted metalloproteases Adamts5 , Adamts20 ( bt ), and Adamts9 result in fully penetrant soft-tissue... |
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| SubjectTerms | ADAM Proteins - deficiency ADAM Proteins - genetics ADAM Proteins - metabolism ADAMTS Proteins ADAMTS5 Protein ADAMTS9 Protein Animals Apoptosis Biological and medical sciences Body Patterning Calcium-Binding Proteins - metabolism Cell differentiation, maturation, development, hematopoiesis Cell physiology CELLCYCLE DEVBIO Extremities - embryology Fundamental and applied biological sciences. Psychology Gene Expression Regulation, Developmental Gene Expression Regulation, Enzymologic Mice Mice, Knockout Molecular and cellular biology SIGNALING Versicans - metabolism |
| Title | ADAMTS Metalloproteases Generate Active Versican Fragments that Regulate Interdigital Web Regression |
| URI | https://dx.doi.org/10.1016/j.devcel.2009.09.008 https://www.ncbi.nlm.nih.gov/pubmed/19922873 https://www.proquest.com/docview/734147708 https://pubmed.ncbi.nlm.nih.gov/PMC2780442 |
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