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  • Although the presence of at least one


    Although the presence of at least one triple helix domain is typically the collagen signature, collagens are modular proteins composed of a succession of collagenous (COL) and non-collagenous domains (NC) that are both involved in collagen functions and in receptor binding. COL domains are linked by short linker regions of about 20 residues, while larger NC domains are found at the N- and/or C-terminal ends of the α-chains and can represent more than two-third of the entire collagen molecule (Fig. 2C). Protein sequence alignments revealed that NC domains are generally well conserved in zebrafish [3,19,34,39,44] but their specific functions in zebrafish await further studies. Collagen molecules undergo a series of post-translational modifications both intracellularly and extracellularly that are most often mediated by key enzymatic activities, as the collagen prolyl 4-hydroxylases (P4Hs) and the lysyl-hydroxylases (LHs) that both reside within the endoplasmic reticulum and the lysyl oxidase (LOX), a matrix crosslinking enzyme (Fig. 2B). Most of the post-translational modifications are shared with all collagen types, but specificities exist. In zebrafish such modifications are also present. For instance, the plod2 mutant carrying a mutation in the lysyl-hydroxylase-2 encoding gene showed a severe disruption of the three-dimensional collagen I fibril network in vertebral bones [51]. Another hallmark is the extremely large size of collagen molecules, the huge amount of collagen molecules that are secreted in the extracellular space in a very short time window and their rapid secretion during development or repair. The secretory vesicles have to accommodate the large size of collagen molecules. It has been shown that the fibrillar collagens are transported from the ER to the FRAX597 in a COPII (coat protein II complex)-dependent manner. Additional ER associated proteins were shown to assist collagen macromolecules transport into vesicular carriers. Specifically, the auxiliary protein Sar1 and the recruited heterodimers Sec23/Sec24 proteins are proven to be essential for vesicle biogenesis and collagen molecule exportation [52]. Interestingly, collagen trafficking is impaired in the crusher/sec23a mutant. This prevents collagen II secretion and causes severe cartilage defects [53]. The feelgood mutant also manifests severe skeletal defects. Melville and co-workers [54] reported that the feelgood mutation causes a single amino acid substitution within the sequence encoding the DNA-binding domain of transcription factor Creb3l2, which specific targets are genes encoding the COPII proteins sec23a, sec23b and sec24d. Despite intracellular accumulation of collagen, no activation of ER stress response genes was observed [54].
    Collagen function(s) in zebrafish development Among the zebrafish community, collagen genes were first valued as tissue markers. For instance, the col10a1 gene, encoding collagen X, was first reported as a reliable marker of both osteoblasts and chondrocytes in zebrafish [55] and the col2a1 gene was commonly used as a notochord marker in early embryos [38]. Finally collagen I genes were used to probe fibrosis as in all vertebrates [56,57]. Thanks to the development of gene modulation technologies (morpholino (MO)-knockdown, mutagenesis, transgenesis and targeted genome editing), the description of collagen expression patterns and the investigation of collagen gene functions in developing zebrafish embryos have largely expanded, giving significant insights into their functional diversity and most importantly, the underlying mechanisms (Table 1). The generation of specific antibodies to the zebrafish proteins has proven, in our lab and others, to be instrumental for the analysis of collagen function in developing zebrafish [19,31,32,34,56,58] (Table 1). The recent generation of fluorescent collagen I-fusion zebrafish lines represents unique tools to investigate collagen dynamics [59] and opens up new avenue for the study of collagen biosynthesis and remodelling in living animals. Our objective here was to report on the main advances in collagen function research, and we now apologize that other important functional studies have not been quoted due to word limitation.