The a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs (ADAMTS) family of metzincins are complex secreted proteins that have diverse functions during development. The hyalectanases (ADAMTS1, 4, 5, 8, 9, 15 and 20) are a subset of this family that have enzymatic activity against hyalectan proteoglycans, the processing of which has important implications during development. This review explores the evolution, expression and developmental functions of the ADAMTS family, focusing on the ADAMTS hyalectanases and their substrates in diverse species. This review gives an overview of how the family and their substrates evolved from non-vertebrates to mammals, the expression of the hyalectanases and substrates in different species and their functions during development, and how these functions are conserved across species.

INTRODUCTION

The a disintegrin-like and metalloproteinase with thrombos-pondin type-1 motifs (ADAMTS) proteinases belong to the M12B subfamily of the metzincin (zinc-dependent metalloproteinase) superfamily of complex secreted enzymes [1,2]. The ADAMTS family, of which there are 19 members in mammals (Figure 1), have crucial and wide-ranging functions as illustrated by the demonstrated role of several members in human disease. For example, ADAMTS2 mutations cause Ehlers–Danlos syndrome type VIIC, ADAMTS10 mutations cause recessive Weill–Marchesani syndrome, ADAMTS13 mutations cause thrombocytopenic purpura (TTP) and ADAMTS17 mutations cause Weill–Marchesani-like syndrome [36]. The related ADAMTS-like (ADAMTSL) proteins, which lack catalytic function (Figure 1), also play important roles in disease. Thus, mutations in ADAMTSL2 cause geleophysic dysplasia and ADAMTSL4 mutations cause ectopia lentis [7,8]. Conditions resulting from mutations in ADAMTS and ADAMTSL genes have been recently reviewed in detail [9].

Structure of the ADAMTS and ADAMTS-like proteins

Figure 1
Structure of the ADAMTS and ADAMTS-like proteins

The ADAMTS proteinases contain a protease domain responsible for their enzymatic activity as well as an ancillary domain. The pro-domain of the hyalectanases (ADAMTS1, 4, 5, 8, 9, 15 and 20) requires cleavage from the catalytic domain to expose the zinc ion to its substrate proteoglycans such as versican and aggrecan. The ADAMTS-like (ADAMTSL) proteins contain only an ancillary domain. The ancillary domains consist of a variety of sequence motifs, as indicated.

Figure 1
Structure of the ADAMTS and ADAMTS-like proteins

The ADAMTS proteinases contain a protease domain responsible for their enzymatic activity as well as an ancillary domain. The pro-domain of the hyalectanases (ADAMTS1, 4, 5, 8, 9, 15 and 20) requires cleavage from the catalytic domain to expose the zinc ion to its substrate proteoglycans such as versican and aggrecan. The ADAMTS-like (ADAMTSL) proteins contain only an ancillary domain. The ancillary domains consist of a variety of sequence motifs, as indicated.

The so-called ‘hyalectanases’ represent a conserved subset of ADAMTS proteins that show proteolytic activity towards the hyalectan/lectican class of proteoglycans, and include ADAMTS1, ADAMTS4 (aggrecanase-1), ADAMTS5/11 (aggrecanase-2), ADAMTS8, ADAMTS9, ADAMTS15 and ADAMTS20 (Figure 1) [1,10]. The hyalectanases all share a highly conserved N-terminal region containing a signal peptide, a propeptide and a catalytic domain (Figure 1). Removal of the propeptide occurs either before or after secretion into the extracellular matrix (ECM) [1], depending upon the hyalectanase [11,12]. Experiments to identify precise in vivo locations for pro-domain removal have not been done in most cases, and distinguishing events which occur intracellularly, on the cell surface or extracellularly is not insignificant. Nonetheless, it is interesting that removal of the pro-domain of ADAMTS9 appears to reduce its activity, consistent with a unique intracellular function for this clade member [13].

The ancillary domain of the ADAMTS hyalectanases is required for substrate recognition, as well as correct tissue compartmentalization (Figure 1) [11,14]. The ancillary domain of ADAMTS enzymes and ADAMTSL proteins contain a disintegrin-like domain, cysteine-rich domain, spacer region, as well as a variable number of thrombospondin (TSP) type-1 motifs with additional domains found in some members (Figure 1). A recent review further details the characteristic structural features of the ADAMTS family [15]. Several ADAMTS proteinases are modified by proteolysis in their ancillary domains, potentially altering substrate recognition and localization [16,17]. For example, ADAMTS1 processing in the ancillary domain may modulate its anti-angiogenic properties [17]. Proteolysis in the ancillary domain may be autocatalytic, although other proteases may also be involved. For example, glycosylphosphatidyl-inositol-anchored membrane type-4 matrix metalloproteinase (MT4-MMP) cleaves ADAMTS4 in its C-terminal domain, enabling cell-surface activation [18]. In addition, the fragments released by ancillary domain cleavage may have biological functions independent of catalytic activity. For example, a C-terminal fragment of ADAMTS18 induced oxidative platelet fragmentation, to potentially protect against carotid artery occlusion and stroke [19].

All hyalectanases are predicted to contain a variety of post-translational modifications including N-glycosylation, O-fucosylation and C-mannosylation [12]. To date, N-glycosylation sites have been confirmed in ADAMTS1, ADAMTS5, ADAMTS9 and ADAMTS15 [12,13,20,21], with O-fucosylation and C-mannosylation sites demonstrated in ADAMTS5 [22]. These modifications may be essential for secretion from the cell. For example, mutation of the putative ADAMTS5 N-glycosylation sites at N728, N802 and N807 to glutamine by site-directed mutagenesis increased the electrophoretic mobility of ADAMTS5, whereas its secretion into the extracellular environment was reduced [22]. The role of O-fucosylation and C-mannosylation modifications is largely unknown, although secretion of ADAMTSL1 (Punctin) was found to be inhibited upon removal of O-fucosylation and C-mannosylation sites [22,23]. A previous review further details the post-translational modifications described for the hyalectanases [12].

The ADAMTS hyalectanases show preferred proteolytic activity towards the hyalectan family of proteoglycans, which comprise aggrecan, versican, neurocan and brevican [24]. The hyalectans share an N-terminal G1 domain with a signal peptide, a chondroitin sulfate (CS) or glycosaminoglycan (GAG) region, and a C-terminal G3 domain [25]. The G1 domain of the hyalectans includes a hyaluronan (HA)-binding motif (present in other hyaladherins such as tumour necrosis factor-inducible gene 6 protein) through which each can bind to HA [24,26]. Versican exists in several isoforms, full-length (V1–often referred to as ‘V0’ in the literature [27]), and the shorter forms V2 (also called ‘V1’ [27]), V3 (also called ‘V2’ [27]) and V4 (also called ‘V3’ [28]), with another form, V5 (also called ‘V4’ [29]), more recently discovered. Cleavage in vivo of aggrecan [30], versican isoforms (V1, V2 and V3) [3133] and brevican [34] by one or more of the ADAMTS hyalectanases occurs at E-X motifs. Such cleavage near the G1 domain(s) generate the HA-binding products G1-NITEGE, G1-DPEAAE, G1-NIVSFE and G1-ESE of aggrecan, versican V1/V2, versican V3 and brevican respectively. There is no equivalent E-X site in neurocan and preliminary studies suggest that it is primarily cleaved in the middle of the core protein, although no sequence data are available [35]. Cleavage of aggrecan and/or versican by ADAMTS8 and ADAMTS15 has been shown in enzyme incubation and transfection systems only [21,36,37], and a previous review provides further details of potentially redundant hyalectan degradation by the ADAMTS hyalectanase clade [38].

EVOLUTION OF THE ADAMTS FAMILY

The ADAMTS family and its hyalectan substrates have been investigated across a variety of organisms. Members of the ADAMTS family have been found in invertebrates such as Caenorhabditis elegans and Drosophila melanogaster, with their hyalectan substrates found in vertebrates. This evidence has provided important evolutionary insights–including evidence of both conservation and diversification between lineages–but also information related to the progressive complexity of the ECM in vertebrates.

C. elegans possesses an ADAMTS orthologue known as gon-1, responsible for gonadal morphogenesis. This demonstrates greatest similarity to mammalian ADAMTS9 and ADAMTS20 [39,40] that contain almost identical structures, consisting of 15 TSP type-1 repeats and the unique GON-1 region [39]. It has also been shown that gon-1 and ADAMTS9 share the ability to promote protein transport from the endoplasmic reticulum (ER) to the Golgi apparatus [41], with ADAMTS9 (and ADAMTS4) able to substitute for gon-1 in nematodes [39,42]. Collectively, this suggests functional conservation of these hyalectanases throughout evolution, with derivation from a common ancestor related to gon-1. Three other C. elegans ADAMTS orthologues have been discovered, known as mig-17, adt-1 and adt-2 (Figure 2) [4345]. Of these, the encoded adt-1 and adt-2 were the most divergent and not found in insects or vertebrates, whereas mig-17 also has no vertebrate equivalent (Figure 2). These are likely to have evolved independently with unique functions, such as the role of adt-1 in C. elegans ray morphogenesis [43].

Evolution of the ADAMTS family

Figure 2
Evolution of the ADAMTS family

C. elegans has four ADAMTS family members, MIG-17, GON-1, ADT-1 and ADT-2 (boxed, yellow text), Drosophila has three, ADAMTS-A, CG4096 and Stall (boxed, white text), whereas mammals have 19 members, ADAMTS1–10 and 12–20 (ovals, black text). All genes have been derived from a common ancestor related to gon-1. This was duplicated to yield a distinct lineage not found in mammals, comprising three C. elegans genes and Drosophila stall. The gon-1-related gene duplicated to yield a lineage containing Drosophila adamts-a and the mammalian hyalectanases (circled) and a lineage containing Drosophila cg4096 and the remaining mammalian genes.

Figure 2
Evolution of the ADAMTS family

C. elegans has four ADAMTS family members, MIG-17, GON-1, ADT-1 and ADT-2 (boxed, yellow text), Drosophila has three, ADAMTS-A, CG4096 and Stall (boxed, white text), whereas mammals have 19 members, ADAMTS1–10 and 12–20 (ovals, black text). All genes have been derived from a common ancestor related to gon-1. This was duplicated to yield a distinct lineage not found in mammals, comprising three C. elegans genes and Drosophila stall. The gon-1-related gene duplicated to yield a lineage containing Drosophila adamts-a and the mammalian hyalectanases (circled) and a lineage containing Drosophila cg4096 and the remaining mammalian genes.

The D. melanogaster genome encodes three ADAMTS family members [46]. The most closely related to mammalian ADAMTS9, ADAMTS20 and the rest of the hyalectanase group is adamts-a (Figure 2) [46]. A negative feedback regulator of epidermal growth factor receptor (EGFR), cg4096, was found to be most similar to the ADAMTS7 and ADAMTS12 (Figure 2) [46,47], as well as ADAMTS6, ADAMTS10, ADAMTS16, ADAMTS17, ADAMTS18 and ADAMTS19 (Figure 2). The other member, stall, was most closely related to C. elegans mig-17, a lineage seemingly lost in vertebrates [46,48].

The ascidian Ciona intestinalis, a urochordate that represents the closest extant relative of vertebrates, was found to contain six ADAMTS genes [49,50]. The encoded proteins each cluster with two or more mammalian proteins: adamtsa related to ADAMTS2, ADAMTS3 and ADAMTS14, adamtsb related to ADAMTS16 and ADAMTS18, adamtsc related to ADAMTS7 and ADAMTS12, adamtsd related to ADAMTS9 and ADAMTS20, adamtse related to ADAMTS6 and ADAMTS10 and adamtsf related to ADAMTS1, ADAMTS4, ADAMTS5, ADAMTS8 and ADAMTS15. The mammalian genes, therefore, appear to be derived from common ancestors to these urochordate genes that have each been duplicated at least once during the two successive whole genome duplications that have occurred during mammalian evolution [51]. In contrast, ADAMTS13, ADAMTS17 and ADAMTS19 have either arisen after the divergence of urochordates, or represent a lineage(s) lost in urochordates.

The majority of mammalian ADAMTS genes have been found to be conserved in zebrafish (Danio rerio) [51]. However, the genes encoding ADAMTS4 and ADAMTS19 are not present, although the latter is found in the gar (Lepisosteus aculeatus) genome [51], suggesting that it was lost along the teleost lineage. However, zebrafish have two orthologues for ADAMTS2 (adamts2a and adamts2b), ADAMTS8 (adamts8a and adamts8b) and ADAMTS15 (adamts15a and adamts15b), which are likely to be the result of an additional whole genome duplication event in teleost fish [5052]. These additional orthologues may have taken on additional functions to compensate for the loss of other members [51]. However, the generally high conservation across vertebrate species suggests both that the ADAMTS genes are likely to be of critical importance, and that further analysis of their functions in one vertebrate will be informative to other vertebrate species.

The ADAMTSL family are rooted by single C. elegans and C. intestinalis genes, designated ce-punctin/madd-4 and adamtsg respectively [50]. The latter is derived from an ancestral gene that has subsequently expanded by a combination of local and whole genome duplication to yield the six mammalian ADAMTSL members [50]. Single zebrafish orthologues exist for both ADAMTSL4 and ADAMTSL5 each but there are two and three orthologues, respectively, for Papilin and ADAMTSL2 [50]. Six additional zebrafish ADAMTSL genes, adamtslaadamtslf have no direct mammalian orthologues [50]. The diversification of the ADAMTSL family during teleostean evolution, again through a combination of local and whole genome duplication, suggests that the ADAMTSL family have probably taken on specialized functions in this lineage.

EXPRESSION OF THE ADAMTS HYALECTANASES

The expression patterns of ADAMTS enzymes and their substrates have been determined across a number of species, and throughout development. This has provided useful insights into their biological roles and functional interactions.

Zebrafish adamts1 mRNA was detected throughout embryogenesis and was abundant in adult skeletal muscle, brain and eye, and also detected in the heart, spleen and skin (Table 1) [51]. The mRNA of the Xenopus laevis ADAMTS1 orthologue XAdamts1 was detected in the presumptive ectoderm, the Spemann organizer and later in the trunk organizer region and posterior ectoderm of the developing embryo (Table 1) [53]. High levels of Adamts1 mRNA were detected in the mouse yolk sac, placenta, brain, limb bud, lung, liver, heart and kidney from E10 (E is embryonic day) to E18, specifically in the smooth muscle of the alveolar sac of the lung (E14–E16), distal and proximal tubules of the kidney (E16) and digital interzone of the limb bud (E12) (Table 1) [54]. Adamts1 mRNA was highly up-regulated in the ovary during rat ovulation [55], consistent with Adamts1 mRNA detected in follicular somatic cells for teleost fish, mouse, cow and Xenopus (Table 1) [51,56]. Human ADAMTS1 mRNA was detected in the aorta, bladder, cervix and uterus, but also in ovary, brain and heart (Table 1) [57].

Table 1
Expression pattern of the hyalectanases by species

Overview of the characterized tissue expression patterns for ADAMTS hyalectanase family members in different species. C. elegans GON-1 and D. melanogaster ADAMTS-A are included under ADAMTS9 and X. laevis XADAMTS1 is included under ADAMTS1. The majority of these studies have analysed gene expression of the hyalectanases with protein expression less understood. C. elegans: roundworm; D. melanogaster: fruit fly; D. rerio: zebrafish; X. laevis: African clawed frog; M. musculus: house mouse; H. sapiens: human.

Hyalectanase Species Tissue expression Gene or protein Time point Reference(s) 
ADAMTS1 D. rerio Skin, skeletal muscle, brain, eye, thymus, heart, kidney, gut, testes, oocytes, spleen Gene Embryo: one-cell stage until 7 dpf, adult [51
 X. laevis Sensorial layer, presumptive ectoderm, dorsal and ventral mesoderm, brain, branchial arches, notochord, presumptive dermatome, heart anlage, pronephros, Spemann organizer and trunk organizer region, posterior ectoderm, follicular somatic cells Gene Embryo: gastrulation, neurulation, tail bud [53
 M. musculus Placenta, spleen, yolk sac, limb bud, brain, lung, liver, heart, kidney Gene Embryo: E10–E18, adult [54
 H. sapiens Heart, brain, skeletal muscle, placenta, aorta, bladder, cervix, colon, oesophagus, liver, ovary, prostate, small intestine, spinal cord, stomach, uterus, cartilage Gene Adult [57
ADAMTS4 M. musculus Ovary, telencephalic oligodendrocytes, adipose tissue Gene and protein Adult [5860
 H. sapiens Aorta, bladder, heart, brain, lung, liver, placenta, skeletal muscle, spinal cord, ovary, uterus, cervix, colon, oesophagus, prostate, small intestine, stomach, cartilage Gene Adult [57
ADAMTS5 D. rerio Skin, skeletal muscle, brain, eye, thymus, heart, liver, kidney, gut, testes, oocytes, spleen Gene Embryo: one-cell stage until 7 dpf, adult [51
 M. musculus Floor plate, skeletal muscle, dorsal root ganglia, nerves, interdigital and craniofacial mesenchyme, brain, lung, arteries, gut, kidney, heart Gene and protein Embryo: E9.5–E16.5, adult [61
 H. sapiens Aorta, bladder, heart, brain, lung, liver, placenta, skeletal muscle, spinal cord, ovary, uterus, cervix, colon, oesophagus, prostate, small intestine, stomach, cartilage Gene Adult [57
ADAMTS8 D. rerio Skin, liver, skeletal muscle, kidney, gut, brain, eye, thymus, heart, oocytes, testes, spleen Gene Embryo: one-cell stage until 7 dpf, adult [51
 M. musculus Lung, heart Gene Adult [62
ADAMTS9 C. elegans (GON-1) Leader cells, muscle Gene L1 until adult stage [63
 D. melanogaster (ADAMTS-A) Haemocytes, caudal visceral mesoderm, visceral branch of the trachea, secretory portion of the salivary gland Gene Embryo: stage 8 until stage 16 [46
 D. rerio Cerebellum, rhombic lip, skeletal muscle, eye, brain, thymus, skin, heart, kidney, gut, testes, oocytes, spleen Gene Embryo: one-cell stage until 7 dpf, adult [51
 M. musculus Heart, brain, spleen, lung, liver, skeletal muscle, kidney, thymus, cartilage, trophoblast, parietal endoderm, allantois, capillaries, endothelium, mesoderm, aorta, diaphragm, ventral body wall, stomach, intestines, pancreas, gonad, bladder, mandible, ear, salivary gland Gene Embryo: E7.5–E17.5 [39,64
 H. sapiens Heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testes, ovary, small intestine, colon, skin fibroblast, leucocytes Gene Fetus, adult [39
ADAMTS15 D. rerio (adamts15a) Branchial arch I and II, Meckel's cartilage, skin, skeletal muscle, brain, eye, thymus, heart, liver, kidney, gut, testes, oocytes, spleen Gene Embryo: 8 hpf until 7 dpf (adamts15b: one-cell stage until 24 hpf and 7 dpf), adult [51
 M. musculus Heart, perichondrium, whisker follicles, brain, epidermis, ear, lung, cartilage, skeletal muscle, skin, nerves, small intestine, chondrocytes, interneurons Gene and protein Embryo: E10.5–E15.5, adult [21,59
ADAMTS20 M. musculus Melanoblasts, midbrain, brain, testes Gene and protein Embryo: E12.5, adult [65,66
 H. sapiens As for ADAMTS9, breast Gene Adult [39
Hyalectanase Species Tissue expression Gene or protein Time point Reference(s) 
ADAMTS1 D. rerio Skin, skeletal muscle, brain, eye, thymus, heart, kidney, gut, testes, oocytes, spleen Gene Embryo: one-cell stage until 7 dpf, adult [51
 X. laevis Sensorial layer, presumptive ectoderm, dorsal and ventral mesoderm, brain, branchial arches, notochord, presumptive dermatome, heart anlage, pronephros, Spemann organizer and trunk organizer region, posterior ectoderm, follicular somatic cells Gene Embryo: gastrulation, neurulation, tail bud [53
 M. musculus Placenta, spleen, yolk sac, limb bud, brain, lung, liver, heart, kidney Gene Embryo: E10–E18, adult [54
 H. sapiens Heart, brain, skeletal muscle, placenta, aorta, bladder, cervix, colon, oesophagus, liver, ovary, prostate, small intestine, spinal cord, stomach, uterus, cartilage Gene Adult [57
ADAMTS4 M. musculus Ovary, telencephalic oligodendrocytes, adipose tissue Gene and protein Adult [5860
 H. sapiens Aorta, bladder, heart, brain, lung, liver, placenta, skeletal muscle, spinal cord, ovary, uterus, cervix, colon, oesophagus, prostate, small intestine, stomach, cartilage Gene Adult [57
ADAMTS5 D. rerio Skin, skeletal muscle, brain, eye, thymus, heart, liver, kidney, gut, testes, oocytes, spleen Gene Embryo: one-cell stage until 7 dpf, adult [51
 M. musculus Floor plate, skeletal muscle, dorsal root ganglia, nerves, interdigital and craniofacial mesenchyme, brain, lung, arteries, gut, kidney, heart Gene and protein Embryo: E9.5–E16.5, adult [61
 H. sapiens Aorta, bladder, heart, brain, lung, liver, placenta, skeletal muscle, spinal cord, ovary, uterus, cervix, colon, oesophagus, prostate, small intestine, stomach, cartilage Gene Adult [57
ADAMTS8 D. rerio Skin, liver, skeletal muscle, kidney, gut, brain, eye, thymus, heart, oocytes, testes, spleen Gene Embryo: one-cell stage until 7 dpf, adult [51
 M. musculus Lung, heart Gene Adult [62
ADAMTS9 C. elegans (GON-1) Leader cells, muscle Gene L1 until adult stage [63
 D. melanogaster (ADAMTS-A) Haemocytes, caudal visceral mesoderm, visceral branch of the trachea, secretory portion of the salivary gland Gene Embryo: stage 8 until stage 16 [46
 D. rerio Cerebellum, rhombic lip, skeletal muscle, eye, brain, thymus, skin, heart, kidney, gut, testes, oocytes, spleen Gene Embryo: one-cell stage until 7 dpf, adult [51
 M. musculus Heart, brain, spleen, lung, liver, skeletal muscle, kidney, thymus, cartilage, trophoblast, parietal endoderm, allantois, capillaries, endothelium, mesoderm, aorta, diaphragm, ventral body wall, stomach, intestines, pancreas, gonad, bladder, mandible, ear, salivary gland Gene Embryo: E7.5–E17.5 [39,64
 H. sapiens Heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testes, ovary, small intestine, colon, skin fibroblast, leucocytes Gene Fetus, adult [39
ADAMTS15 D. rerio (adamts15a) Branchial arch I and II, Meckel's cartilage, skin, skeletal muscle, brain, eye, thymus, heart, liver, kidney, gut, testes, oocytes, spleen Gene Embryo: 8 hpf until 7 dpf (adamts15b: one-cell stage until 24 hpf and 7 dpf), adult [51
 M. musculus Heart, perichondrium, whisker follicles, brain, epidermis, ear, lung, cartilage, skeletal muscle, skin, nerves, small intestine, chondrocytes, interneurons Gene and protein Embryo: E10.5–E15.5, adult [21,59
ADAMTS20 M. musculus Melanoblasts, midbrain, brain, testes Gene and protein Embryo: E12.5, adult [65,66
 H. sapiens As for ADAMTS9, breast Gene Adult [39

In the mouse, ADAMTS4 (and ADAMTS5) protein identified through immunohistochemistry was detected in follicular granulosa cells of follicles prior to ovulation (Table 1) [58]. Following ovulation, ADAMTS4 (along with ADAMTS1) protein was detected in different cell types, including within the highly vascular site of follicle rupture, endothelial cells of corpora lutea and cumulus cells within the ovulated cumulus cell–oocyte complex [58]. Adamts4 mRNA was exclusively detected in telencephalic oligodendrocytes during myelination, therefore corresponding to an important aspect of neuronal development in the mouse [59]. Furthermore, ADAMTS4 (and ADAMTS5) protein identified through Western blot analysis was expressed in subcutaneous and gonadal adipose tissue in mice [60]. ADAMTS4 mRNA was detected in adult human heart, brain, lung, liver, placenta, skeletal muscle, spinal cord, ovary and uterus [57], although lower in most tissues compared with ADAMTS1 (Table 1) [57].

Zebrafish adamts5 mRNA was detected at all time points during embryogenesis [51]. However, the transcript was most abundant between 8 and 24 h post-fertilization (hpf), corresponding to gastrulation, somitogenesis and organogenesis (Table 1) [51]. Expression of adamts5 mRNA was detected in most zebrafish adult organs including heart, brain, eye, thymus, kidney and gut with the transcript most abundant in the liver (Table 1) [51]. Adamts5 mRNA and protein identified through immunohistochemistry was also detected during mouse embryogenesis, from E11.5 in the central and peripheral nervous systems, from E13.5 in the musculoskeletal system, in the interdigital mesenchyme and perichondrium surrounding the digit skeleton in forelimbs and hindlimbs as well as in skeletal myoblasts, which differentiate to give rise to muscle cells (Table 1) [61]. Adult mice Adamts5 mRNA was detected in the mesangial cells of the kidney glomeruli, cardiac and hepatic endothelial cells, as well as glial and Schwann cells of the central and peripheral nervous systems respectively (Table 1) [61]. ADAMTS5 mRNA was most highly detected in human placenta, uterus, cervix and oesophagus, with weaker detection in the brain, liver, prostate, skeletal muscle and heart (Table 1) [57].

Zebrafish adamts8a and adamts8b mRNA was also detected throughout embryogenesis (Table 1) [51]. Following low maternal levels, transcript levels of adamts8a peaked at 24 hpf with moderate levels at 7 days post-fertilization (dpf), whereas transcript levels of adamts8b peaked at 8 and 24 hpf, (Table 1) [51]. In the adult, adamts8a was most abundant in the liver, skeletal muscle and kidney but also detected in the brain, heart and oocytes (Table 1) [51]. Adamts8 mRNA was reported to be detected at low levels throughout mouse embryonic development and in adult mouse lung and heart (Table 1) [62].

In C. elegans, gon-1 mRNA was found to be detected in two sites: leader cells and muscle (Table 1) [63]. Drosophila adamts-a mRNA was detected in multiple migratory cell types, including haemocytes, caudal visceral mesoderm, the visceral branch of the trachea and the secretory portion of the salivary gland (Table 1) [46]. In zebrafish, adamts9 mRNA was detected throughout embryogenesis, with the highest levels evident at 8 and 24 hpf, and with specific detection in the cerebellum at 18 and 22 hpf and in the rhombic lip at 22 hpf (Table 1) [51]. Furthermore, adamts9 was detected in adult zebrafish tissues, with highest levels in skeletal muscle, eye and brain (Table 1) [51]. Adamts9 mRNA was also detected during most stages of mouse gestation such as in fetal cartilage, heart, spleen and kidney (Table 1) [39]. At E7.5, Adamts9 mRNA was detected in trophoblast giant cells and the parietal endoderm, and in maternal tissues such as in the arterial wall and endothelium of the uterine artery (Table 1) [64]. At E9.5, Adamts9 was detected in the first branchial arch, head mesoderm near the optic vesicle and in the common ventricle (Table 1) [64]. At E11.5–E12.5, Adamts9 was detected in the forelimb, maxilla, umbilical cord, ventral tail mesoderm, ventral body wall and the artery of the second branchial arch (Table 1) [64]. At E13.5–E14.5, Adamts9 was detected in the rib and sternal perichondrium, genital tubercle, aorta, gonad and hindlimb (Table 1) [64]. Later on during gestation at E17.5, Adamts9 was detected in the craniofacial mesenchyme, lung and mandible (Table 1) [64]. At E12.5, mRNA of the highly related Adamts20 was detected in the midbrain and melanoblasts, but in the adult, ADAMTS20 protein identified through Western blot analysis and mRNA was detected in the brain and testes (Table 1) [65,66]. In adult human tissues, ADAMTS9 mRNA levels were higher than ADAMTS20 in most tissues, especially in the heart, pancreas, placenta, kidney and skin fibroblasts (Table 1) [39]. However, ADAMTS20 transcript levels were higher in leucocytes than ADAMTS9 [39].

Zebrafish adamts15a and adamts15b mRNA were detected during embryogenesis, but adamts15a was largely restricted to 24 hpf onwards being first observed in the first and second pharyngeal arches (24, 48 and 52 hpf) and Meckel's cartilage (80 hpf) and later in the adult kidney, liver, thymus, heart, skeletal muscle and spleen (Table 1) [51]. In contrast, adamts15b transcript levels were more evident during the earlier stages of development, from the one-cell stage until 24 hpf (Table 1) [51]. In mice, Adamts15 mRNA expression was observed in the developing heart (E10.5), perichondrium, whisker follicles, ear, vertebrae and brain (E13.5) (Table 1) [21]. Specifically, ADAMTS15 protein was detected through immunohistochemistry at E11.5 in tissues such as the right atrium, myocardium and airway epithelia (Table 1) [21]. At E14.5, ADAMTS15 was detected in the dorsal root ganglia, and at E15.5 ADAMTS15 was detected in the epidermis, joint capsule, cartilage primordium of the patella and chondrocytes (Table 1) [21]. ADAMTS15 was also detected in the adult mouse intestine (Table 1) [21]. Furthermore, Adamts15 mRNA was detected exclusively in interneurons during synaptogenesis in the mouse [59].

EVOLUTION AND EXPRESSION OF THE HYALECTANS

No orthologues have been found for many ECM components including the hyalectans in C. elegans or Ciona [67]. It is therefore most probable that these genes evolved de novo during early vertebrate evolution and were expanded through whole genome and/or local duplication to attain their specialized roles. Zebrafish possess two aggrecan genes, acana and acanb [52], and two versican genes, vcana and vcanb [52,68]. It remains unknown as to whether the ADAMTS hyalectanase cleavage site is conserved in the products of the acana and acanb genes. However, zebrafish dermacan (encoded by vcanb) has been discovered to be homologous across all regions of human full-length versican (V1 also called ‘V0’), including the N-terminal region that is known to be cleaved by ADAMTS hyalectanases [68]. The cleavage site targeted by ADAMTS hyalectanases, DPEAAEA, was also conserved in zebrafish dermacan, represented by the sequence VAEQEA [52], although it remains to be determined whether dermacan is remodelled by ADAMTS hyalectanases during zebrafish development. In contrast, zebrafish vcana comprises only a small portion of the equivalent mammalian versican, containing just the G3 globular domain [52]. Genes encoding neurocan (ncana and ncanb) and brevican (bcana) have been identified in zebrafish, but their functional roles and whether ADAMTS hyalectanase cleavage sites are conserved remain unknown [52].

In terms of the hyalectan substrates, zebrafish aggrecan (acana) mRNA was detected in the pharyngeal arch, neurocranium and the pectoral fin during development [68], and both mRNA and protein identified through immunohistochemistry was also detected in the peri-notochordal sheath and notochord [69,70]. In chick embryos, aggrecan mRNA and protein identified via Western blot analysis and immunohistochemistry was detected in the heart, especially at later stages of development in mesenchymal cells, epicardium, heart valves, the sino-atrial junction and the basement membrane of the notochord [71]. Furthermore, aggrecan protein identified through immunohistochemistry was detected in the heart valves of the chick embryo, specifically in the fibrosa, spongiosa and annulus and postnatally in the fibrosa and spongiosa [72]. In mice, aggrecan mRNA and protein identified via immunohistochemistry were detected in embryonic brain glia [73]. During mouse development, aggrecan mRNA and protein identified through immunohistochemistry were detected in the limb bud cartilage [74]. Aggrecan gene expression was identified in embryonic and postnatal cortex and spinal cord in the adult rat [75]. In this study, aggrecan mRNA and protein detected via Western blot analysis and immunohistochemistry were specifically identified in neurons in the perineuronal net [75]. In adult mice, aggrecan mRNA was expressed in subcutaneous and gonadal adipose tissue [60], as well as postnatal and adult cartilage [76,77], and aggrecan protein identified through Western blot analysis and immunohistochemistry was detected in skin [78]. Furthermore, aggrecan (and versican) protein detected via Western blot analysis was identified in the intervertebral disc of adult sheep [79], and both mRNA and protein identified through immunohistochemistry were detected in the anterior and posterior cruciate ligaments, articular cartilage and meniscus of adult dog [80]. Aggrecan mRNA and protein identified via Western blot analysis and immunohistochemistry were detected in the sclera of the adult human eye [81]. Aggrecan gene expression was also identified in differentiated mesenchymal stem cells derived from adult human bone marrow [82].

Zebrafish versican (vcana) was detected during embryonic development including in adaxial mesoderm, lateral plate mesoderm lining and circulatory precursor cells, and more laterally in paraxial mesoderm, as well as in the heart, lens and otic vesicle [68]. Zebrafish dermacan (vcanb) mRNA was detected during embryonic dermal bone development in structures such as the sclerotome, tail fin bud, otic vesicle and craniofacial bones, such as the opercle and dentary, and near the midbrain [68]. In Xenopus embryos, versican mRNA was detected during gastrulation and neurulation, as well as in the neural crest cells, pronephros and heart [83]. In chick embryos, versican mRNA was detected in the heart early in development, whereby its expression was evident throughout the myocardium, the basement membrane between the myocardium and endocardium and the sino-atrial junction via in situ hybridization [71]. Versican mRNA was also detected in the neural tube, notochord and sclerotome of the developing chick [84]. Versican mRNA was detected at E13, E14 and E18 in mouse embryos [85]. Furthermore, versican protein identified through immunostaining was detected in mouse embryonic craniofacial structures, such as the tooth mesenchyme, mandible and maxilla; at E13.5–E14, versican was readily detected in the palatal mesenchyme, the strongest being towards the nasal cavity [86]. Versican was also detected in the heart at E10.5, pectoral girdle at E10.5–E12.5, stylopod precartilage core and future elbow at E11.5–E14.5 muscle and in the autopod at E12.5–14.5 shown through β-galactosidase and versican antibody staining [87]. Versican mRNA was detected in adult mouse brain, lung, heart, spleen, tail and skin, with lower levels detected in the liver, kidney and testes [85]. Furthermore, versican protein identified through immunohistochemistry was detected in human adult tissues such as blood vessels, tendon, cartilage, lung alveoli, skin, gastrointestinal and respiratory tracts, adrenal cortex, thyroid follicles, uterus, prostate and cerebellum [88].

Brevican and neurocan were found to be predominately central nervous system (CNS)-restricted hyalectans and synthesized by glial cells and neurons as reviewed previously [89]. In Xenopus, brevican mRNA was detected in the brain and notochord during early embryogenesis [90]. Brevican protein identified through the slot-blot immunoassay was detected in the embryonic rat brain at low levels and increased steadily after birth to a level 14-fold higher than during embryogenesis [91]. Brevican gene and protein identified through Western blot analysis and immunohistochemistry were detected in the adult rat and bovine brain where they was localized extracellularly [92,93]. Furthermore, brevican protein detected via Western blot analysis and immunohistochemistry was identified in the adult mouse cerebellum and perineuronal nets [94]. Neurocan mRNA and protein identified through Western blot analysis and immunohistochemistry was detected in the embryonic avian heart and vasculature, although later it was restricted to the CNS along with brevican, at least in birds [89,95]. In mouse embryos, neurocan protein detected via immunohistochemistry was observed in the retina and chiasmatic neurons [96]. Neurocan protein identified through immunocytochemistry, along with aggrecan and versican protein, was detected in mouse neural stem cells and neural cells [97]. Neurocan mRNA was isolated from the adult and early postnatal rat brain [98] and neurocan protein detected via immunohistochemistry was found in the rat optic nerve [99] and postnatal rat hippocampus [100]. Although by no means an exhaustive list of hyalectan expression, these data suggest that, despite the function of the hyalectans being conserved in several respects, they also show specificity for developmental stage, tissue type and, although not the focus of this review, pathology.

ADAMTS HYALECTANASES AND THE HYALECTANS IN DEVELOPMENT

Independently, or in co-operation, the ADAMTS hyalectanases have pronounced roles during development. However, whether these are proteolytic and/or non-proteolytic roles is unclear. A recent review described versican proteolysis by hyalectanase(s) developmentally [31]. This section will expand on this to cover all developmental roles of the hyalectanases and hyalectans.

The C. elegans ADT-1 was shown to be necessary for morphogenesis of the male copulatory organs [43], and MIG-17 in remodelling the basement membrane to direct migration of distal tip cells in the gonad [45]. Moreover, Adamts1−/− mice displayed impaired ovarian folliculogenesis and infertility linked to decreased versican cleavage [101,102]. This indicates a conserved role for ADAMTS proteins in the development and maintenance of the reproductive organs. Adamts1−/− mice also presented with kidney dysgenesis and interstitial fibrosis evident at birth, leading to the death of almost half of Adamts1−/− pups neonatally, although the surviving embryos largely escape adverse effects from the kidney deformity [103,104]. However, this phenotype was exacerbated in Adamts1−/−; Adamts4−/− combinatorial knockout mice with most of the mice dying within 72 h after birth due to prominent renal medulla thinning, despite Adamts4−/− mice not presenting with a kidney phenotype [105,106]. Therefore, Adamts1 and Adamts4 appear to act in a partially redundant manner in kidney development. Adamts4−/−; Adamts5−/− combinatorial knockout mice have been generated, but no additional phenotypes were observed [61,107,108]. Adamts5, Adamts9 and Adamts20 were co-expressed (with versican) and co-operate to stimulate interdigital apoptosis, forming the penatameric digits, also with versican cleavage in the interdigital mesenchyme [108,109]. Additionally, Adamts5-deficient mice present with myxomatous heart valves, apparently concurrent with decreased immunoreactive versican cleavage fragments and increased full-length versican. However, Western blot analysis of valve extracts will be needed to definitively establish this association [110]. ADAMTS5 appears to play a non-redundant and non-proteolytic role in reducing cellular glucose uptake and hyalectan synthesis by mesenchymal stem cells [111], consistent with the observations that Adamts5−/− mice deposit increased levels of aggrecan in skin [78], tendon [112] and joints [113] in response to injury. Currently, there are no published Adamts8- or Adamts15-knockout mice to ascertain the roles of these family members in development.

Adamts9+/−; Adamts20−/− mice present with a fully penetrant secondary cleft palate [114]. Additionally, Adamts9+/−; Adamts20−/− and Adamts20−/− mice exhibit a defect in melanoblast colonization and survival, with a reduction in versican cleavage at the site of depigmentation [65]. Adamts9−/− mice show embryonic lethality around E7.5, prior to cardiovascular development [114]. However, Adamts9+/− mice present with cardiac anomalies such as chondrogenic nodules and myxomatous heart valves, associated with versican accumulation [65,115]. Furthermore, conditionally targeted mice have revealed the non-redundant role of ADAMTS9 in interdigital web regression and differentiation of umbilical cord vascular smooth muscle [109,116]. Interestingly, the C. elegans gon-1 ADAMTS gene has been found to be essential for reproduction, being responsible for migration of distal tip cells during gonadal morphogenesis [40], whereas adamts-a was required for cell migration during embryogenesis [46]. These data are suggestive of a conserved role for the members of the ADAMTS9/ADAMTS20 clade in cell migration.

It has been demonstrated that aggrecan was involved in chondrogenesis and gangliogenesis in the chick brain, consistent with findings in mice [73,77,82,84,117]. Furthermore, in mice, aggrecan was found to be involved in formation of growth plate cytoarchitecture and differentiation [118], as well as preadipocyte differentiation and adipose tissue development [60]. Hyalectanase-mediated degradation of aggrecan and versican appears to play a role in matrix turnover of injured joints, skin and tendon in mice [78,111]. However, E-X cleavage occurs in these tissues in the absence of ADAMTS5. This clearly indicates that ADAMTS5 alone is not responsible for the E-X cleavage observed, findings that are at odds with the popular understanding that ADAMTS5 is primarily responsible for aggrecan degradation in arthritis models [119,120]. In addition, dermacan-knockdown zebrafish showed decreased ossification in dermal bones, suggesting an important role in bone development [68]. Versican V0 and V1 isoforms have been shown to guide migratory neural crest cells, and versican has a role during synovial joint morphogenesis in the chick embryo [121123], data consistent with the findings obtained from zebrafish and mouse [68,124,125]. Conditional versican knockout mice (Prx1-Cre/Vcanflox/flox) displayed distorted digits, hypertrophic chondrocytic nodules in their cartilage, joint tilting and delayed chondrocytic differentiation in digits, suggesting that versican facilitates joint morphogenesis and chondrogenesis [125]. Furthermore, versican has an important role during mouse heart development [126,127]. Indeed, versican-deficient (hdf−/−) mice die during gastrulation from a heart defect [124].

Brevican up-regulation and subsequent promotion of glial cell motility has been associated with glioma invasion through in vitro studies [89,128131]. However, there are no definitive data suggestive of a non-redundant role of the hyalectanases in brevican turnover. Furthermore, brevican has been shown to moderate neuronal adhesion and growth during development by binding to neural cell adhesion molecules in rat cells [132]. Analysis of neurocan-knockout mice has revealed that neurocan is dispensable for brain development [133]. However, neurocan was involved in modulating rat retinal vasculature [134]. Neurocan up-regulation may also occur in disease such as rat retinal ischaemia and chronic CNS glial scarring in rats, and has been linked to schizophrenia and bipolar disorders in humans [135138]. Furthermore, mice deficient in both brevican and neurocan have the capacity to restore sensory function following brachial plexus injury [139]. It is evident that more is known about the roles of brevican and neurocan in pathology than development, however, it is clear that they have CNS-specific functions during development.

In most studies in which ADAMTS is ablated or mutated, it is probable that the phenotypes are attributable to a lack of enzymatic activity against particular substrates, with evidence described in this review. However, direct linkage is difficult to ascertain given that analysis of enzymatic activity in vivo is challenging. Therefore some contention exists as to whether only one substrate or ADAMTS is involved, whether the enzyme is specific towards the substrate and whether there may be non-catalytic roles for the ADAMTS in these cases. An interesting field of study in future will be the analysis of possible non-proteolytic activities of the ADAMTS hyalectanases, as already described for some of them. For example, ADAMTS1 was shown to bind to VEGF through its C-terminal thrombospondin repeats and spacer domain to block VEGFR2 activation [140]. Furthermore, proteolysis was not required for enhancement of neurite outgrowth by ADAMTS4, which was instead dependent on mitogen-activated protein kinase (MAPK) cascade activation [141]. A recent study also demonstrated that ADAMTS5 knockout promoted glucose uptake and synthesis of chondroitin sulfate on aggrecan and versican V2 by adipose-derived stromal cells. Biosynthetic studies showed that hyalectanase-mediated degradation of aggrecan and versican was not due to ADAMTS5, but to one or more other ADAMTS hyalectanases with the capacity to cleave these substrates before the addition of CS chains in the trans-Golgi [111]. Moreover, wild-type and catalytically inactive (E363A) ADAMTS15 reduced breast cancer cell migration on matrices of fibronectin or laminin, attenuated by the knockdown of syndecan-4 [36]. Although this is an emerging field of study that is not well-understood, non-catalytic roles of the ADAMTS hyalectanases should not be discounted from further studies.

CONCLUSION

The field of matrix biology has progressed substantially in its five decade history with the discovery of the ADAMTS family making a significant contribution. Indeed, a vast array of developmental and disease processes have been found to be regulated by the ADAMTS proteinases and the related ADAMTSL proteins [142,143]. However, the ADAMTS family remains less well characterized compared with their MMP counterparts.

Mouse knockouts have been mainly utilized to study the ADAMTS hyalectanase substrates. Increasingly, conditional or gene-trap targeted mice are being used, especially those such as ADAMTS9 and versican, where knockouts are embryonic lethal [109,114,116,125]. However, studies regarding the evolution of the ADAMTS hyalectanases and their substrates have paved the way for alternative animal models to be utilized in analysing roles of the ADAMTS family during embryogenesis [51]. Among these, the zebrafish has emerged as an important alternative model [144]. The Zebrafish Mutation Project by the Sanger Institute has already generated several ADAMTS and ADAMTSL mutants. Furthermore, zebrafish are more readily accessible for the application of genome-editing technologies such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated systems (Cas) to facilitate effective gene manipulation [145149]. An exciting prospect is the analysis of ADAMTS family members that are otherwise lethal, such as ADAMTS9, or have not yet been characterized, such as ADAMTS8. In addition, the accessible and transparent embryos of zebrafish allow for new approaches to study these proteins. For example, techniques have now been developed to label active MMPs in living zebrafish, which is capable of providing unprecedented data regarding dynamic ECM remodelling during vertebrate embryogenesis that may be applied to the ADAMTS hyalectanases [150,151]. The use of zebrafish and other alternative vertebrate models will underpin the further elucidation of the roles of ADAMTS and ADAMTSL family members during embryogenesis and in disease.

We thank Professor Suneel Apte for his helpful advice regarding the paper.

FUNDING

This work was supported by the Financial Markets Foundation for Children [grant number 2014-058 (to A.C.W. and D.R.M.)].

Abbreviations

     
  • ADAMTS

    a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs

  •  
  • ADAMTSL

    ADAMTS-like

  •  
  • CNS

    central nervous system

  •  
  • CRISPR

    clustered regularly interspaced short palindromic repeats

  •  
  • CS

    chondroitin sulfate

  •  
  • dpf

    days post-fertilization

  •  
  • E

    embryonic day

  •  
  • ECM

    extracellular matrix

  •  
  • GAG

    glycosaminoglycan

  •  
  • HA

    hyaluronan

  •  
  • hpf

    h post-fertilization

  •  
  • MMP

    matrix metalloproteinase

  •  
  • TSP

    thrombospondin

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