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-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.
McCulloch
Daniel R
DR
Department of Biomedical Engineering, Lerner Research Institute, ND20-Cleveland Clinic, Cleveland, OH 44195, USA.
Nelson
Courtney M
CM
Dixon
Laura J
LJ
Silver
Debra L
DL
Wylie
James D
JD
Lindner
Volkhard
V
Sasaki
Takako
T
Cooley
Marion A
MA
Argraves
W Scott
WS
Apte
Suneel S
SS
D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071096:ADAMTS Proteins; D000071116:ADAMTS5 Protein; D000071119:ADAMTS9 Protein; D000818:Animals; D017209:Apoptosis; D019521:Body Patterning; D002135:Calcium-Binding Proteins / Q000378:metabolism; D005121:Extremities / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D018345:Mice, Knockout; D053675:Versicans / Q000378:metabolism*
D002135:Calcium-Binding Proteins; C060820:fibulin; D053675:Versicans; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; D000071116:ADAMTS5 Protein; D000071119:ADAMTS9 Protein; C479569:Adamts20 protein, mouse; C498489:Adamts5 protein, mouse; C545434:Adamts9 protein, mouse