title: Collagen XVIII/endostatin is essential for vision and retinal pigment epithelial function.
abstract: Age-related macular degeneration (ARMD) with abnormal deposit formation under the retinal pigment epithelium (RPE) is the major cause of blindness in the Western world. basal laminar deposits are found in early ARMD and are composed of excess basement membrane material produced by the RPE. Here, we demonstrate that mice lacking the basement membrane component collagen XVIII/endostatin have massive accumulation of sub-RPE deposits with striking similarities to basal laminar deposits, abnormal RPE, and age-dependent loss of vision. The progressive attenuation of visual function results from decreased retinal rhodopsin content as a consequence of abnormal vitamin A metabolism in the RPE. In addition, aged mutant mice show photoreceptor abnormalities and increased expression of glial fibrillary acidic protein in the neural retina. Our data demonstrate that collagen XVIII/endostatin is essential for RPE function, and suggest an important role of this collagen in Bruch's membrane. Consistent with such a role, the ultrastructural organization of collagen XVIII/endostatin in basement membranes, including Bruch's membrane, shows that it is part of basement membrane molecular networks.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA, USA. alexander_marneros@hms.harvard.edu
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Marneros
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.forename: Uwe
authors.initials: U
authors.lastname: Hansen
authors.forename: Naomi
authors.initials: N
authors.lastname: Fukai
authors.forename: Karen
authors.initials: K
authors.lastname: Moulton
authors.forename: Patrice L
authors.initials: PL
authors.lastname: Goletz
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Moiseyev
authors.forename: Basil S
authors.initials: BS
authors.lastname: Pawlyk
authors.forename: Willi
authors.initials: W
authors.lastname: Halfter
authors.forename: Sucai
authors.initials: S
authors.lastname: Dong
authors.forename: Masao
authors.initials: M
authors.lastname: Shibata
authors.forename: Tiansen
authors.initials: T
authors.lastname: Li
authors.forename: Rosalie K
authors.initials: RK
authors.lastname: Crouch
authors.forename: Peter
authors.initials: P
authors.lastname: Bruckner
authors.forename: Bjorn R
authors.initials: BR
authors.lastname: Olsen
mesh_terms: D000375:Aging; D000818:Animals; D015153:Blotting, Western; D016570:Bruch Membrane / Q000737:chemistry / Q000648:ultrastructure; D002645:Chickens; D043170:Collagen Type XVIII / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000648:ultrastructure; D004596:Electroretinography / Q000187:drug effects; D043169:Endostatins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008268:Macular Degeneration / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D010857:Pigment Epithelium of Eye / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D017434:Protein Structure, Tertiary; D012160:Retina / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D012243:Rhodopsin / Q000032:analysis; D012867:Skin / Q000737:chemistry / Q000166:cytology; D014785:Vision, Ocular; D014801:Vitamin A / Q000494:pharmacology
chemical_list: D043170:Collagen Type XVIII; D043169:Endostatins; D005904:Glial Fibrillary Acidic Protein; D014801:Vitamin A; D012243:Rhodopsin