title: Collagen XVIII short isoform is critical for retinal vascularization, and overexpression of the Tsp-1 domain affects eye growth and cataract formation.
abstract: OBJECTIVE
  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 medium/long isoforms, caused aberrant retinal vascularization.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Oulu Center for Cell-Matrix Research, Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Aikio
authors.forename: Merja
authors.initials: M
authors.lastname: Hurskainen
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Brideau
authors.forename: Pasi
authors.initials: P
authors.lastname: Hägg
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.forename: Ritva
authors.initials: R
authors.lastname: Heljasvaara
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Gould
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D002386:Cataract / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D043170:Collagen Type XVIII / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D016133:Polymerase Chain Reaction; D012160:Retina / Q000378:metabolism / Q000648:ultrastructure*; D015861:Retinal Neovascularization / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019700:Thrombospondin 1 / Q000096:biosynthesis / Q000235:genetics*; D041623:Tomography, Optical Coherence
chemical_list: D043170:Collagen Type XVIII; D019700:Thrombospondin 1; D004247:DNA
keywords: Knobloch syndrome; buphthalmos; collagen XVIII; phthisis bulbi; retinal vascularization