Crumbs homologue 1 is required for maintenance of photoreceptor cell polarization and adhesion during light exposure.

Serge A Van De Pavert,Jan Wijnholds,Penny Rashbass,Jan Klooster,Inge Versteeg,Christiaan Levelt,Mathias W Seeliger,Albena Kantardzhieva,Jan Meuleman,Anna Malysheva,Sylvia Geiger,Andre Le Bivic

doi:10.1242/jcs.01301

Abstract

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.

Highlights

Mutations causing amino acid substitutions in the human Crumbs homologue 1 (CRB1) gene, the human homologue of Drosophila Crumbs, can lead to Leber congenital amaurosis (LCA), classic and retinitis pigmentosa type 12, and retinitis pigmentosa with Coats-like exudative vasculopathy (Cremers et al, 2002; den Hollander et al, 1999; van Soest et al, 1999), whereas all known null mutations lead to LCA
Crb1 localizes 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 membrane palmitoylated protein 4 (Mpp4)
Crb2, Crb3 and Crb1 interacting proteins remain localized to the sub-apical region and are not sufficient to maintain cell adhesion during light exposure in Crb1–/– retinas

Summary

Introduction

Mutations causing amino acid substitutions in the human Crumbs homologue 1 (CRB1) gene, the human homologue of Drosophila Crumbs, can lead to Leber congenital amaurosis (LCA), classic and retinitis pigmentosa type 12, and retinitis pigmentosa with Coats-like exudative vasculopathy (Cremers et al, 2002; den Hollander et al, 1999; van Soest et al, 1999), whereas all known null mutations lead to LCA. LCA is a group of inherited severe retinal diseases characterized by loss of vision within one year after birth. It accounts for at least 5% of all retinal dystrophies and is one of the main causes of blindness in children (Cremers et al, 2002). The CRB1 protein contains 19 epidermal growth factor-like domains, three laminin A globular-like domains, a transmembrane domain and a 37 amino acid cytoplasmic tail with an C-terminal ERLI motif (den Hollander et al, 1999; Tepass et al, 1990)

Methods

Results

Discussion

Conclusion