Composition and function of the Crumbs protein complex in the mammalian retina

Abstract

The Crumbs proteins (CRBs) are transmembrane proteins, homologous to Drosophila Crumbs, with a key role in defining the apical membrane domain in photoreceptors as well as in embryonic epithelia. Crumbs proteins are conserved between species and their intracellular domains are involved in organizing a conserved macromolecular protein scaffold with important roles in cell polarity as well as morphogenesis and maintenance of the retina. Mutations in the gene encoding human CRB1, the first one identified out of the three human orthologs, have been associated with a number of retinal dystrophies including Leber amaurosis and retinitis pigmentosa type 12. Although no other mammalian Crumbs complex members as of yet have been associated with retinal degeneration, disruption of different zebrafish and fruitfly orthologs can lead to various retinal defects. The core Crumbs complex localizes apical to the outer limiting membrane, where photoreceptors and Müller glia contact each other. Correct functioning of Crumbs ensures adhesion between these cells by an unknown mechanism. This review summarizes the current view on the composition and function of the Crumbs prsotein complex in the mammalian retina. Recently, a number of new members of the Crumbs protein complex have been identified. These include most members of the membrane palmitoylated protein family (MPP), involved in assembly of macromolecular protein complexes. Some components of the complex are found to exert a function in the photoreceptor synapses and/or at the region of the connecting cilium. Studies using polarized cell cultures or model organisms, like Drosophila and zebrafish, suggest important links of the Crumbs protein complex to several biological processes in the mammalian eye, including retinal patterning, ciliogenesis and vesicular transport.

A self-renewing division of zebrafish Müller glial cells generates neuronal progenitors that require N-cadherin to regenerate retinal neurons

“…Because the injury mechanism is different in the two lesion paradigms, the time course of neuronal damage and degeneration is not necessarily the same, and a major difference is that apical processes of Müller glia form adherens junctions with photoreceptors at the OLM (Gosens et al, 2008). Damage to photoreceptors disrupts the adherens junctions, which are important regulators of differentiation and proliferation in radial glia (Götz and Huttner, 2005).…”

Transcriptional regulation of cell polarity in EMT and cancer

“…At present, there are three CRB, two Pals and one PATJ gene known to exist in humans (Assemat et al, 2008). The composition and function of the CRB complex in the mammalian retina have been recently reviewed (Gosens et al, 2008), where mutations in the human CRB1 gene cause autosomal recessive retinitis pigmentosa and autosomal Leber congenital amaurosis (Richard et al, 2006). The mammalian SCRIB complex is localized in the basolateral domain of epithelial cells and it is comprised of three proteins, Scribble (Scrib), Disc large (Dlg) and Lethal giant larvae (Lgl) (reviewed by Vasioukhin, 2006).…”

The Crumbs complex: from epithelial-cell polarity to retinal degeneration

“…Mutations in human CRB1 (OMIM 600105) are associated with a variety of autosomal-recessive retinal dystrophies (den Hollander et al, 2008). These include retinitis pigmentosa (RP) with preserved para-arteriolar retinal pigment epithelium (PPRPE), RP with Coatslike exudative vasculopathy, early onset RP without PPRPE, and Leber congenital amaurosis (LCA).…”

“…Most of these transiently interacting proteins are conserved not only in their domain organisation, but also in the nature of their interactions with other proteins in the Crumbs complex. We refer to recent reviews for extensive descriptions of additional links between the Crumbs complex and other protein networks (Assémat et al, 2008;Gosens et al, 2008;Macara, 2004). The presence of several orthologues of each fly protein in the complex greatly increases its variability in vertebrates, but at the same time it makes their analysis more difficult owing to possible functional redundancy.…”

“…CRB3 has a completely different extracellular domain to the other CRB proteins. This domain contains only 56 amino acids and has no sequence similarity to that of the other CRB proteins; however, because the cytoplasmic domain is highly conserved, it is considered to be a member of the Crb protein family (reviewed by Gosens et al, 2008;Richard et al, 2006b). Vertebrate genomes encode three Lin7 genes and two PATJ genes, PATJ and MUPP1 (multi-PDZ-domain protein).…”