title: ADAMTS metalloproteases generate active versican fragments that regulate interdigital web regression.
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.
authors.affiliation: Department of Biomedical Engineering, Lerner Research Institute, ND20-Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McCulloch
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Nelson
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Dixon
authors.forename: Debra L
authors.initials: DL
authors.lastname: Silver
authors.forename: James D
authors.initials: JD
authors.lastname: Wylie
authors.forename: Volkhard
authors.initials: V
authors.lastname: Lindner
authors.forename: Takako
authors.initials: T
authors.lastname: Sasaki
authors.forename: Marion A
authors.initials: MA
authors.lastname: Cooley
authors.forename: W Scott
authors.initials: WS
authors.lastname: Argraves
authors.forename: Suneel S
authors.initials: SS
authors.lastname: Apte
mesh_terms: 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*
chemical_list: 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