ADAMTS Metalloproteases Generate Active Versican Fragments that Regulate Interdigital Web Regression

• Published in: Developmental cell Vol. 17; no. 5; pp. 687 - 698
• Main Authors: McCulloch, Daniel R., Nelson, Courtney M., Dixon, Laura J., Silver, Debra L., Wylie, James D., Lindner, Volkhard, Sasaki, Takako, Cooley, Marion A., Argraves, W. Scott, Apte, Suneel S.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 17.11.2009; Cell Press
• Subjects: 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; CELLCYCLE; DEVBIO; SIGNALING; Development; Regression; Regulation(control)
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2009.09.008

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.