WH-4-023 The dermal ECM also shows specificities During zebr
The dermal ECM also shows specificities. During zebrafish embryogenesis, the epidermis is composed of the outer periderm and the inner basal keratinocytes, which are responsible for the initial deposition of ECM in the primitive acellular dermis .The dermal endothelial cells, a species-specific cell type located at the interface between dermis and hypodermis, were shown to also contribute to the production of the developing dermal ECM. After metamorphosis (20–26 dpf), when juveniles seem miniature versions of the adults, fibroblast-like WH-4-023 progressively invade the dermis. The epithelial ECM production ceases and dermal fibroblasts take over the synthesis and deposition of the collagen fibrils . While dermis in mammals is composed of collagen fibrils showing no preferential orientation, the dermal ECM of the zebrafish comprises regular orthogonal layers of collagen fibrils  (Fig. 1B). Strikingly, this plywood-like structure is reminiscent to the mammalian corneal stroma whose principal role is to contribute to the transparency of the cornea. The strict orthogonal organization of the dermal ECM might contribute, in the same way, to its optical transparency. Along this line, the deposition by basal epithelial cells of a primary stroma containing orthogonal layers of collagen fibrils, that act as a template for subsequent ECM deposition by invading fibroblasts, reminds us the development of the chick corneal stroma . The development and physiology of cartilage and bones are highly similar in mammals and teleosts validating the zebrafish as a reliable vertebrate model in this field . Expression of genes and the molecular pathways involved in the endochondral ossification are well conserved. For instance, as in mammals, Sox9, a key regulator of chondrogenesis was shown to regulate genes encoding cartilage-specific ECM in zebrafish embryos . As such, the cartilage-specific collagens (types II, IX and XI) and proteoglycan, aggregan, and the main matricellular proteins, as matrillins and chondromodulin, are expressed in the zebrafish cartilage (review in Luderman et al. ). At the ultrastructural level, the organization and distribution of collagen and proteoglycan networks are highly similar to mammalian ECM cartilage (Fig. 1A). Dermal bones that develop from the direct differentiation of mesenchymal cells into osteoblasts (a process known as intramembranous ossification) are found in fin rays, scales and gill covers . The skeleton of zebrafish fins comprises the segmented parenthesis-shaped dermal bones called lepidotrichia and the unsegmented non-mineralized distal structures of ectodermal origin, the actinotrichia. Lepidotrichia is different from any other skeletal tissue that appears to be the result of a unique combination of collagen genes required for its development. Notably, col10a1, known as a specific marker of hypertrophic chondrocytes in higher vertebrates is expressed in the zebrafish bony rays . Actinotrichia are composed of collagen fibrils and non-collagenous proteins that aggregate into supramolecular structure referred to as elastoidin . The nature of the ECM constituents of the zebrafish scales is less defined and the current knowledge on the matrix organization of the scales comes almost exclusively from TEM studies . Elasmoid scales, the scale type of zebrafish and medaka, start to develop at 26 dpf, when fibroblast-like cells from which derived the scale-forming cells invade the dermis [27,28]. These mineralized structures made of orthogonal layers of collagen fibrils and elasmodin develop within the dermis and protrude into the epidermis. But the limiting layer of the scale, close to the epidermis, is devoid of collagen fibrils . The trunk of the zebrafish embryo consists of a characteristic chevron-shaped block of muscles separated by the vertical myosepta. These thin connective tissue sheets transmit muscular forces to axial structures during swimming. In that, they are structurally and functionally equivalent to mammalian tendons. Muscle fibers insert into the myoseptal connective tissue via a highly specialized region referred to as the myotendinous junction (MTJ) [29,30]. The zebrafish MTJ is highly similar to that observed in mammals . Specifically, this structure displays finger-like folds that increase contact between muscle and the adjacent myosepta (Fig. 1C). Ultrastructural studies showed that myosepta remain acellular until 72 hours post-fertilisation (hpf) , suggesting that muscle cells are responsible for the synthesis and deposition of the ECM components present in the myosepta (mainly composed of collagen I fibrils) and the MTJ which contains BM zone components such as laminins and fibronectin , collagen XV-B  and the MTJ marker collagen XXII . Later in development, fibroblasts are observed in myosepta and their presence coincides with the production of a dense network of collagen fibrils and the subsequent thickening of the myosepta . The myoseptal fibroblasts were reported to express the classical collagenous tendon markers, collagens I and XII [33,34]. Even though their composition is highly similar, the ECM organization in myosepta and tendons are different. While mammalian tendons are composed of parallel bundles of collagen fibers, myosepta consist of tightly packed collagen fibers with an oblique arrangement adapted to the undulatory swimming of the fish (Fig. 1C).