Crumbs homologue 1 is required for maintenance of photoreceptor cell polarization and adhesion during light exposure.
Loss of Crumbs homologue 1 (CRB1) function causes either the eye disease Leber congenital amaurosis or progressive retinitis pigmentosa, depending on the amount of residual CRB1 activity and the genetic background. Crb1 localizes specifically to the sub-apical region adjacent to the adherens junction complex at the outer limiting membrane in the retina. We show that it is associated here with multiple PDZ protein 1 (Mupp1), protein associated with Lin-7 (Pals1 or Mpp5) and Mpp4. We have produced Crb1(-/-) mice completely lacking any functional Crb1. Although the retinas are initially normal, by 3-9 months the Crb1(-/-) retinas develop localized lesions where the integrity of the outer limiting membrane is lost and giant half rosettes are formed. After delamination of the photoreceptor layer, neuronal cell death occurs in the inner and outer nuclear layers of the retina. On moderate exposure to light for 3 days at 3 months of age, the number of severe focal retinal lesions significantly increases in the Crb1(-/-) retina. Crb2, Crb3 and Crb1 interacting proteins remain localized to the sub-apical region and therefore are not sufficient to maintain cell adhesion during light exposure in Crb1(-/-) retinas. Thus we propose that during light exposure Crb1 is essential to maintain, but not assemble, adherens junctions between photoreceptors and Müller glia cells and prevents retinal disorganization and dystrophy. Hence, light may be an influential factor in the development of the corresponding human diseases.
The Netherlands Ophthalmic Research Institute, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
Serge A
SA
van de Pavert
Albena
A
Kantardzhieva
Anna
A
Malysheva
Jan
J
Meuleman
Inge
I
Versteeg
Christiaan
C
Levelt
Jan
J
Klooster
Sylvia
S
Geiger
Mathias W
MW
Seeliger
Penny
P
Rashbass
Andre
A
Le Bivic
Jan
J
Wijnholds
D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D001766:Blindness / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology / Q000528:radiation effects; D002450:Cell Communication / Q000502:physiology / Q000528:radiation effects; D002462:Cell Membrane / Q000378:metabolism; D016764:Cell Polarity / Q000502:physiology* / Q000528:radiation effects; D006801:Humans; D008027:Light; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D010775:Photic Stimulation; D020419:Photoreceptor Cells, Vertebrate / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects*; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism*; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; C453730:Crb1 protein, mouse; C119588:LIN-7 protein, mammalian; D008565:Membrane Proteins; C491750:Mpdz protein, mouse; D009419:Nerve Tissue Proteins