Dermal connective tissue development in mice: an essential role for tenascin-X

Abstract

Deficiency of the extracellular matrix protein tenascin-X (TNX) causes a recessive form of Ehlers-Danlos syndrome (EDS) characterized by hyperextensible skin and hypermobile joints. It is not known whether the observed alterations of dermal collagen fibrils and elastic fibers in these patients are caused by disturbed assembly and deposition or by altered stability and turnover. We used biophysical measurements and immunofluorescence to study connective tissue properties in TNX knockout and wild-type mice. We found that TNX knockout mice, even at a young age, have greatly disturbed biomechanical properties of the skin. No joint abnormalities were noted at any age. The spatio-temporal expression of TNX during normal mouse skin development, during embryonic days 13-19 (E13-E19), was distinct from tropoelastin and the dermal fibrillar collagens type I, III, and V. Our data show that TNX is not involved in the earliest phase (E10-E14) of the deposition of collagen fibrils and elastic fibers during fetal development. From E15 to E19, TNX starts partially to colocalize with the dermal collagens and elastin, and in adult mice, TNX is present in the entire dermis. In adult TNX knockout mice, we observed an apparent increase of elastin. We conclude that TNX knockout mice only partially recapitulate the phenotype of TNX-deficient EDS patients, and that TNX could potentially be involved in maturation and/or maintenance of the dermal collagen and elastin network.

Interactions of human tenascin-X domains with dermal extracellular matrix molecules

“…The skin strength in TNX deWcient mice is markedly reduced, although the signiWcance and magnitude of the reduction of collagen deposition is debated [3,15,18]. In mice, the variation in collagen Wbril diameter appears to be increased [15,18].…”

“…We have previously shown TNX to be present in the entire dermis of healthy individuals. During development in mice TNX colocalises with the major Wbrillar collagens and elastic Wbers in the dermis [3,22]. Adult TNX deWcient patients show abnormal elastic Wbers and reduced collagen deposition in skin [28].…”

PDGFRβ Expression and Function in Fibroblasts Derived from Pluripotent Cells is Linked to DNA Demethylation

“…The early events directing cell and tissue repair following injury are dependent on the spatially and temporally controlled production and deposition of ECM proteins by mesenchymal cells and through the recruitment of a variety of cell types through cell migration (Egging et al, 2006;Friedl and Bröcker, 2000). It is known that PDGFRb plays a role during multiple stages of wound healing, because loss of PDGFRb function impairs fibroblast migration (Gao et al, 2005) and stimulation of this receptor by recombinant PDGF-BB accelerates the healing of chronic wounds through deposition of ECM proteins (Pierce et al, 1992;Steed, 1995).…”

Tenascin-X: beyond the architectural function

“…Notably, their dermis shows elastic fibers that are mostly immature, devoid of microfibrils and irregularly shaped. 52 TN-X has also been shown to localize to elastic fibers in vivo 58 and to interact with tropoelastin in vitro through its C-terminal region including the last FNIII domains and the fibrinogen globe. 37 It is also conceivable that TN-X might be involved in elastic fibers formation and maturation.…”

“…37 It is also conceivable that TN-X might be involved in elastic fibers formation and maturation. 29,58 Figure 3. Model of TN-X integration within the collagenous network.…”