Abstract
ADAMTS20 (A disintegrin-like and metalloprotease domain with thrombospondin type-1 motifs) is a member of a family of secreted metalloproteases that can process a variety of extracellular matrix (ECM) components and secreted molecules. Adamts20 mutations in belted (bt) mice cause white spotting of the dorsal and ventral torso, indicative of defective neural crest (NC)-derived melanoblast development. The expression pattern of Adamts20 in dermal mesenchymal cells adjacent to migrating melanoblasts led us to initially propose that Adamts20 regulated melanoblast migration. However, using a Dct-LacZ transgene to track melanoblast development, we determined that melanoblasts were distributed normally in whole mount E12.5 bt/bt embryos, but were specifically reduced in the trunk of E13.5 bt/bt embryos due to a seven-fold higher rate of apoptosis. The melanoblast defect was exacerbated in newborn skin and embryos from bt/bt animals that were also haploinsufficient for Adamts9, a close homolog of Adamts20, indicating that these metalloproteases functionally overlap in melanoblast development. We identified two potential mechanisms by which Adamts20 may regulate melanoblast survival. First, skin explant cultures demonstrated that Adamts20 was required for melanoblasts to respond to soluble Kit ligand (sKitl). In support of this requirement, bt/bt;Kittm1Alf/+ and bt/bt;KitlSl/+ mice exhibited synergistically increased spotting. Second, ADAMTS20 cleaved the aggregating proteoglycan versican in vitro and was necessary for versican processing in vivo, raising the possibility that versican can participate in melanoblast development. These findings reveal previously unrecognized roles for Adamts proteases in cell survival and in mediating Kit signaling during melanoblast colonization of the skin. Our results have implications not only for understanding mechanisms of NC-derived melanoblast development but also provide insights on novel biological functions of secreted metalloproteases.
Highlights
A disintegrin-like and metalloprotease with thrombospondin type-1 motifs (ADAMTS) metalloproteases constitute a large family of 19 zinc-dependent proteolytic enzymes that are distantly related to both the A disintegrin and metalloproteinase (ADAM) family, and to the matrix metalloproteinases (MMPs) [1,2]
In this study we have investigated how mutations in a secreted metalloprotease, Adamts20, result in mice with white belts in their lumbar region, even though Adamts20 is not expressed in the pigment producing cells
Our findings suggest that the belting pattern is due to a combination of increased pigment cell death, decreased pigment cell number in the trunk, and functional overlap of closely related metalloproteases
Summary
A disintegrin-like and metalloprotease with thrombospondin type-1 motifs (ADAMTS) metalloproteases constitute a large family of 19 zinc-dependent proteolytic enzymes that are distantly related to both the A disintegrin and metalloproteinase (ADAM) family, and to the matrix metalloproteinases (MMPs) [1,2]. Some ADAMTS proteases, such as ADAMTS10 (GeneID: 224697), ADAMTS13 (GeneID: 279028), and the procollagen amino-propeptidases (e.g. ADAMTS2), are highly specialized; others process a variety of substrates within the extracellular matrix (ECM), including chondroitin sulfate proteoglycans (CSPGs), such as aggrecan (GeneID: 11595) and versican (GeneID: 13003). Mutation or dysregulation of ADAMTS proteases is associated with inherited and acquired pathologies including Ehlers-Danlos syndrome VIIC (OMIM#225410), thrombocytopenic purpura (OMIM#274150), Weill-Marchesani syndrome (OMIM#277600) and arthritis [5,8,9,10]
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