title: Ultrastructural characterization of developmental and degenerative vitreo-retinal changes in the eyes of transgenic mice with a deletion mutation in type II collagen gene.
abstract: OBJECTIVE
  Molecular genetic analyses have clearly associated vitreoretinal degeneration with mutations in the type II collagen gene, but lack of experimental models has prevented systematic analyses of the occurrence of phenotypic changes and of the pathogenetic mechanisms involved. The present study is a detailed morphological and ultrastructural analysis of the vitreoretinal consequences of a small deletion mutation in the type II collagen gene.
  
  
  METHODS
  The eyes of Del1 mice carrying six copies of pro alpha1(II) collagen transgene with a small deletion mutation were analyzed during embryonic development, postnatal growth and aging using their nontransgenic littermates as controls. Tissue samples were processed for light and electron microscopy for morphological and ultrastructural analyses. Transcription of pro alpha1(II) collagen gene was localized by in situ hybridization, and type II collagen was detected by immunohistochemistry.
  
  
  RESULTS
  In this mouse model most components of the eye are ultrastructurally unaltered. However, the transgenes caused a dose-dependent dominant negative effect seen as a reduced number of type II collagen fibrils in the vitreous. In concert with this, dose-dependent accumulation of amorphous material was observed in the dilated rough endoplasmic reticulum of cells responsible for the production of type II collagen molecules. In mice homozygous for the transgene locus, the vitreoretinal degenerative lesions appeared already during late embryonic development. In mice heterozygous for the locus, such changes were milder and appeared only during postnatal growth and progressed gradually upon aging.
  
  
  CONCLUSIONS
  The observed ultrastructural changes suggest that defective structure and function of collagen fibrils in Del1 mice result from a partial block in the post-translational processing and secretion of the mutated procollagen chains, and partly from secretion of mutated procollagen molecules which interfere with normal fibrillogenesis.
authors.affiliation: Department of Ophthalmology, University of Turku, and Turku University Central Hospital, Turku, Finland.
authors.forename: Tapio
authors.initials: T
authors.lastname: Ihanamäki
authors.forename: Heli
authors.initials: H
authors.lastname: Salminen
authors.forename: Anna-Marja
authors.initials: AM
authors.lastname: Säämänen
authors.forename: Minna
authors.initials: M
authors.lastname: Sandberg-Lall
authors.forename: Eero
authors.initials: E
authors.lastname: Vuorio
authors.forename: Lauri J
authors.initials: LJ
authors.lastname: Pelliniemi
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D024043:Collagen Type II / Q000235:genetics*; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005314:Embryonic and Fetal Development; D005123:Eye / Q000196:embryology; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008822:Mice, Transgenic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000473:pathology / Q000648:ultrastructure*; D014018:Tissue Distribution; D014822:Vitreous Body / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*
chemical_list: D024043:Collagen Type II; D012333:RNA, Messenger