Collagen XVIII/endostatin is essential for vision and retinal pigment epithelial function.
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.
Marneros
Alexander G
AG
Department of Cell Biology, Harvard Medical School, Boston, MA, USA. alexander_marneros@hms.harvard.edu
Keene
Douglas R
DR
Hansen
Uwe
U
Fukai
Naomi
N
Moulton
Karen
K
Goletz
Patrice L
PL
Moiseyev
Gennadiy
G
Pawlyk
Basil S
BS
Halfter
Willi
W
Dong
Sucai
S
Shibata
Masao
M
Li
Tiansen
T
Crouch
Rosalie K
RK
Bruckner
Peter
P
Olsen
Bjorn R
BR
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
D043170:Collagen Type XVIII; D043169:Endostatins; D005904:Glial Fibrillary Acidic Protein; D014801:Vitamin A; D012243:Rhodopsin