Although the Schwann cell basement membrane (BM) is required for normal Schwann cell terminal differentiation, the role of BMassociated collagens in peripheral nerve maturation is poorly understood. Collagen XV is a BM zone component strongly expressed in peripheral nerves, and we show that its absence in mice leads to loosely packed axons in C-fibers and polyaxonal myelination. The simultaneous lack of collagen XV and another peripheral nerve component affecting myelination, laminin ␣4, leads to severely impaired radial sorting and myelination, and the maturation of the nerve is permanently compromised, contrasting with the slow repair observed in Lama4 Ϫ/Ϫ single knock-out mice. Moreover, the Col15a1 Ϫ/Ϫ ;Lama4 Ϫ/Ϫ double knock-out (DKO) mice initially lack C-fibers and, even over 1 year of age have only a few, abnormal C-fibers. The Lama4 Ϫ/Ϫ knock-out results in motor and tactile sensory impairment, which is exacerbated by a simultaneous Col15a1 Ϫ/Ϫ knock-out, whereas sensitivity to heat-induced pain is increased in the DKO mice. Lack of collagen XV results in slower sensory nerve conduction, whereas the Lama4 Ϫ/Ϫ and DKO mice exhibit increased sensory nerve action potentials and decreased compound muscle action potentials; x-ray diffraction revealed less mature myelin in the sciatic nerves of the latter than in controls. Ultrastructural analyses revealed changes in the Schwann cell BM in all three mutants, ranging from severe (DKO) to nearly normal (Col15a1 Ϫ/Ϫ ). Collagen XV thus contributes to peripheral nerve maturation and C-fiber formation, and its simultaneous deletion from neural BM zones with laminin ␣4 leads to a DKO phenotype distinct from those of both single knock-outs.
Type XVIII collagen is important in the early phase of retinal vascular development and for the regression of the primary vasculature in the vitreous body after birth. We show here that the retina in Col18a1-/- mice becomes densely vascularized by anomalous anastomoses from the persistent hyaloid vasculature by day 10 after birth. In situ hybridizations revealed normal VEGF mRNA expression, but the phenotype of collagen XVIII deficient mice closely resembled that of mice expressing VEGF120 and VEGF188 isoforms only, suggesting that type XVIII collagen may be involved in VEGF function. Type XVIII collagen was found to be indispensable for angiogenesis in the eye, as also oxygen-induced neovascularization was less intense than normal in the Col18a1-/- mice. We observed a marked increase in the amount of retinal astrocytes in the Col18a1-/- mice. Whereas the retinal vessels of wild-type mice are covered by astrocytes and the regressing, thin hyaloid vessels are devoid of astrocytes, the retinal vessels in the Col18a1-/- mice were similarly covered by astrocytes but not the persistent hyaloid vessels in the vitreous body. Interestingly, double null mice lacking type XVIII collagen and its homologue type XV collagen had the persistent hyaloid vessels covered by astrocytes, including the parts located in the vitreous body. We thus hypothesize that type XV collagen is a regulator of glial cell recruitment around vessels and that type XVIII collagen regulates their proliferation.
The C-terminal end of collagen XV, restin, has been the focus of several studies, but the functions of full-length collagen XV have remained unknown. We describe here studies on the production, purification, and function of collagen XV and the production of a monoclonal N-terminal antibody to it. Full-length human collagen XV was produced in insect cells using baculoviruses and purified from the cell culture medium. The yield was 15 mg/liter of cell culture medium. The collagen XV was shown to be trimeric, with disulfide bonds in the collagenous region. Rotary shadowing electron microscopy revealed rod-like molecules with a mean length of 241.8 nm and with a globular domain at one end. The globular domain was verified to be the N-terminal end by N-terminal antibody binding. The molecules show flexibility in their conformation, presumably due to the many interruptions in their collagenous domains. The ability of collagen XV to serve as a substrate for cells was tested in cell adhesion assays, and it was shown that cells did not bind to collagen XVcoated surfaces. When added to the culture medium of fibroblasts and fibrosarcoma cells, however, collagen XV rapidly bound to their fibronectin network. Solid phase assays showed that collagen XV binds to fibronectin, laminin, and vitronectin and that it binds to the collagen/gelatin-binding domain of fibronectin. No binding was detected to fibrillar collagens, fibril-associated collagens, or decorin. Interestingly, collagen XV was found to inhibit the adhesion and migration of fibrosarcoma cells when present in fibronectin-containing matrices.Lack of collagen XV in mice leads to the development of skeletal myopathy, collapsed capillaries, and degenerating endothelial cells in the heart and skeletal muscles, suggesting that collagen XV may be important for linking basement membranes to their surrounding tissues (1). Indeed, EM 2 studies have indicated that collagen XV links banded collagen fibers to basement membranes (2).It has been proposed that collagen XV may be involved in the invasiveness of tumors because it is lost in the malignant epithelial basement membranes of colonic adenocarcinomas and ductal carcinomas (3, 4) and because melanocytic nevi and malignant melanomas in situ were positive for collagen XV, whereas melanomas with dermal invasion were negative (5). Recent studies with collagen XV and XVIII double null mice have indicated that collagen XV may also have a regulatory role in inhibiting the migration of astrocytes (6).Collagen XV is a non-fibrillar collagen widely distributed in various tissues, where it has been shown to localize to the basement membrane zones (7-9). Human collagen XV is a homotrimer with ␣ chains composed of 1363 amino acid residues containing a highly interrupted collagenous domain of 577 amino acids flanked by large non-collagenous N-and C-terminal domains of 530 and 256 amino acids, respectively (10, 11). Collagen XV shares structural homology with collagen XVIII, and they together form a subgroup of collagens with their highest ...
An excess of the collagen XVIII Tsp-1 domain is deleterious in the eye, possibly by impairing certain functions of the full-length molecule. Moreover, the short isoform is the critical variant in the development of the posterior eye structures.
Amiodarone is a commonly prescribed and one of the most effective anti-arrhythmic drugs available. However, its use is limited by serious toxic adverse effects including optic neuropathy. Previously, amiodarone-associated optic neuropathy has been reported at an incidence of 1.3%-1.8%. Nearly, one-third of patients with amiodarone-induced toxic optic neuropathy are asymptomatic and typically visual acuity improves after drug cessation. We describe the case of a 75-year-old woman who experienced severe optic neuropathy with bilateral optic disc edema and hemorrhages, irreversible loss of vision, and severe defects in visual fields after 1.5 months use of amiodarone. The optic disc edema resolved promptly after discontinuation of the drug, but the patient remained blind permanently. This is the first report of only 6.5 weeks of amiodarone treatment resulting in bilateral optic neuropathy with bilateral and irreversible loss of vision. To ideally establish a connection between amiodarone and optic neuropathy, re-exposure of the patient to the drug should reproduce the symptoms. As a limitation of the study, this was not done in the present case because it would have been unethical. The worldwide growth of the elderly population in number is expected to increase age-related conditions including cardiac diseases. The use of cardiovascular drugs, also anti-arrhythmic agents such as amiodarone, may increase. Thus, clinicians need to be aware of the possibility of drug-induced toxic optic neuropathy, especially if a patient receiving a regimen of amiodarone complains of visual problems.
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