Collagen XVIII Short Isoform Is Critical for Retinal Vascularization, and Overexpression of the Tsp-1 Domain Affects Eye Growth and Cataract Formation

作者：Mari Aikio, Merja Hurskainen, Gaëlle Brideau, Pasi Hägg, Raija Sormunen, Ritva Heljäsvaara, Douglas B. Gould, Taina Pihlajaniemi · 发表于：Investigative Ophthalmology & Visual Science · 年份：2013 · DOI：10.1167/iovs.13-13039 · 被引用次数：27 · 研究领域：Glaucoma and retinal disorders、Retinal and Macular Surgery、Corneal surgery and disorders

PURPOSE: 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. METHODS: 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. RESULTS: 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 m...