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Mari Aikio, Merja Hurskainen, Gaëlle Brideau, Pasi Hägg, Raija Sormunen, Ritva Heljasvaara, Douglas B. Gould, Taina Pihlajaniemi; Collagen XVIII Short Isoform Is Critical for Retinal Vascularization, and Overexpression of the Tsp-1 Domain Affects Eye Growth and Cataract Formation. Invest. Ophthalmol. Vis. Sci. 2013;54(12):7450-7462. doi: 10.1167/iovs.13-13039.
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Collagen XVIII deficiency leads to anterior and posterior eye defects in Col18a1−/− mice, and overexpression of its C-terminal endostatin domain under a K14 promoter leads to cataract. We studied the consequences of K14-driven overexpression of the thrombospondin-1 (Tsp-1)–like domain, and also the roles of the three collagen XVIII isoforms in mice specifically lacking either the promoter 1–derived short or the promoter 2–derived medium/long isoforms.
Two transgenic lines were generated and compared to Col18a1−/− and promoter 1 and 2 knockouts. Enucleated eyes were analyzed histopathologically, immunohistochemically, biochemically, and ultrastructurally. IOP was measured by noninvasive tonometry, and the anterior chamber was studied in vivo using a slit-lamp and optical coherence tomography.
Overexpression of the Tsp-1 transgene in an FVB/N background resulted in increased axial length, and substantial incidences of cataract, lens subluxation, phthisis, retinal ablation, corneal vascularization, and intraocular hemorrhages. The FVB/N Col18a1−/− mice were affected similarly. The findings in the knockout and transgenic lines were milder in a C57BL/6JOlaHsd (B6) background. Studies with the promoter-specific knockouts revealed the short isoform as the sole variant in the lens capsule and inner limiting membrane, while the ciliary body, iris, and Bruch's membrane contained short and medium/long isoforms. Lack of the short isoform, but not of the medium/long isoforms, caused aberrant retinal vascularization.
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.
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