Proteoglycans are molecules consisting of
protein cores onto which
sugar chains, i.e.,
glycosaminoglycans (GAGs) such as heparan or
chondroitin sulphates, are attached.
Proteoglycans are produced by nearly all cells, and once secreted they become a major component of the extracellular matrix. Cartilage is particularly rich in
proteoglycans, and changes in the structure and composition of GAGs have been found in
osteochondromas and
osteoarthritis. The zebrafish (Danio rerio) exhibits fast development, a growth plate-like organization of its craniofacial skeleton and an availability of various mutants, making it a powerful model for the study of human skeletal disorders with unknown aetiology. We analysed skeletons from five zebrafish lines with known mutations in genes involved in
proteoglycan synthesis: dackel (dak/ext2), lacking heparan sulphate; hi307 (β3gat3), deficient for most GAGs; pinscher (pic/slc35b2), presenting defective sulphation of GAGs and other molecules; hi954 (uxs1), lacking Notch and most GAGs due to impaired
protein xylosylation; and knypek (kny/gpc4), missing the
protein core of the
Glypican-4 proteoglycan. Here we show that each mutant displays different phenotypes related to: (a) cartilage morphology; (b) composition of the extracellular matrix; (c) ultrastructure of the extracellular matrix; and (d) the intracellular ultrastructure of chondrocytes, proving that sulphated GAGs orchestrate the cartilage intra- and extracellular ultrastructures. The mild phenotype of the hi307 mutant suggests that
proteoglycans consisting of a
protein core and a short
sugar linker might suffice for proper chondrocyte stacking. Finally, knypek supports the involvement of
Glypican-4 in the craniofacial phenotype of
Simpson-Golabi-Behmel syndrome and suggests GPC4 as a modulator of the overgrowth phenotype that is associated with this syndrome and is primarily caused by a mutation in GPC3. Moreover, we speculate on the potential involvement of SLC35B2, β3GAT3 and UXS1 in skeletal dysplasias. This work promotes the use of zebrafish as a model of human skeletal development and associated pathologies.