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.