CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina

Abstract

Mutations within the CRB1 gene have been shown to cause human retinal diseases including retinitis pigmentosa and Leber congenital amaurosis. We have recently identified a mouse model, retinal degeneration 8 (rd8) with a single base deletion in the Crb1 gene. This mutation is predicted to cause a frame shift and premature stop codon which truncates the transmembrane and cytoplasmic domain of CRB1. Like in Drosophila crumbs (crb) mutants, staining for adherens junction proteins known to localize to the external limiting membrane, the equivalent of the zonula adherens in the mammalian retina, is discontinuous and fragmented. Shortened photoreceptor inner and outer segments are observed as early as 2 weeks after birth, suggesting a developmental defect in these structures rather than a degenerative process. Photoreceptor degeneration is observed only within regions of retinal spotting, which is seen predominantly in the inferior nasal quadrant of the eye, and is caused by retinal folds and pseudorosettes. Photoreceptor dysplasia and degeneration in Crb1 mutants strongly vary with genetic background, suggesting that the variability in phenotypes of human patients that carry mutations in CRB1 may be due to interactions with background modifiers in addition to allelic variations. The Crb1rd8 mouse model will facilitate the analysis of Crb1 function in the neural retina and the identification of interacting factors as candidate retinal disease genes.

The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration–Like Phenotype

“…Furthermore, it has been reported that photoreceptor degeneration in mice with Crb rd8 mutation strongly varies with the genetic background. 90 Thus, on the basis of these background data and our results with Cd46 À/À fB À/À mice, we conclude that spontaneous age-related degenerative changes in the retina, RPE, and choroid of Cd46 À/À mice are caused by the lack of ocular CD46.…”

Morphological characterization of the retinal degeneration in three strains of mice carrying the rd-3 mutation

“…This focal pattern of RPE cell dropout correlates with the mottled appearance of the fundus reported at 4-6 months postnatally in the pigmented In-30 straiñ Heckenlively et al, 1993a;Hawes et al, 1999;Chang et al, 2002!. Such patterns of hypopigmentation, due to a variety of causes including but not limited to RPE cell dropout, have been seen in fundus photographs of most of the known murine inherited retinal degenerations~Hawes et al, 1999;Chang et al, 2002;Mehalow et al, 2003;Pang et al, 2005!. As we have reported here, several studies correlate areas of RPE cell thinning with the apposing and localized loss of photoreceptor cell bodies comprising the ONL~Caley et al, 1972;Sanyal & Bal, 1973;Sanyal et al, 1980;LaVail et al, 1982LaVail et al, , 1993Blanks et al, 1982;Messer et al, 1993!. As in other photoreceptor degenerations, Müller cells fill in space left by these dying photoreceptors.…”

“…The ability of secondary genes or background to affect the severity of specific retinal inherited degenerations is now appreciated for a number of these allelic variations~Heckenlively et al., 1993a,b;Hawes et al, 1999;Messer et al, 1999;Mehalow et al, 2003;Guarneri et al, 2004!. This is also recognized as an important source of variance in families with respect to disease phenotype.…”

“…is a murine hereditary retinal disorder that may provide an additional model for understanding human inherited retinal degenerations. It is caused by an autosomal recessive gene on chromosome 1, at a totally different locus than the genes associated with the rd~Carter- Dawson et al, 1978!, Rds Sanyal et al, 1980!, pcd, nr~Mullen & LaVail, 1975!, mnd Chang et al, 1994!, tubby~Heckenlively et al, 1995Lamoreux et al, 1992!, rd6~Hawes et al, 2000 Mehalow et al, 2003!, or Rpe65 rd12~P ang et al, 2005generations in mice. Crossbreeding of rd-3/rd-3 mice with mice homozygous for the first six of these mutations produce unaffected offspring~Chang et al, 1993aoffspring~Chang et al, , 1994Heckenlively et al, 1995!. Preliminary studies using both morphological and electroretinogram~ERG!…”

Rôle des protéines Crumbs dans le contrôle de la morphogenèse des cellules épithéliales et des photorécepteurs

“…La protéine CRB1, accumulée dans cette structure, pourrait jouer un rôle dans l'organisation de ces jonctions [38]. Cela est confirmé par l'observation que ces jonctions sont perturbées dans la lignée de souris rd8 qui possède une mutation dans le gène CRB1 [39]. La morphogenèse de la rétine étant normale chez ces souris comme chez les patients, les protéines CRB2 ou CRB3 sont donc capables de compenser une perte de fonction de CRB1.…”