ADAMTS Metalloproteases Generate Active Versican Fragments that Regulate Interdigital Web Regression

Daniel R. McCulloch, Courtney M. Nelson, Laura J. Dixon, Debra L. Silver, James D. Wylie, Volkhard Lindner, Takako Sasaki, Marion A. Cooley, W. Scott Argraves, Suneel S. Apte

Research output: Contribution to journalArticle

156 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)687-698
Number of pages12
JournalDevelopmental Cell
Volume17
Issue number5
DOIs
StatePublished - Nov 17 2009

Keywords

  • CELLCYCLE
  • DEVBIO
  • SIGNALING

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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    McCulloch, D. R., Nelson, C. M., Dixon, L. J., Silver, D. L., Wylie, J. D., Lindner, V., Sasaki, T., Cooley, M. A., Argraves, W. S., & Apte, S. S. (2009). ADAMTS Metalloproteases Generate Active Versican Fragments that Regulate Interdigital Web Regression. Developmental Cell, 17(5), 687-698. https://doi.org/10.1016/j.devcel.2009.09.008