Disease relevance of crb

• A protein with all the characteristics for a Crumbs homologue has been identified from patients suffering from retinitis pigmentosa group 12, but this protein (CRB1) is only expressed in retina and some parts of the brain, both in human and mouse [1].
• Mutations in the Crumbs homologue 1 (CRB1) gene cause autosomal recessive retinitis pigmentosa (arRP) and autosomal Leber congenital amaurosis (arLCA) [2].
• In the present study, we review the current knowledge on Crumbs and its vertebrate homologues, their function in cell polarity and their pathogenicity in retinal degeneration [3].

Psychiatry related information on crb

• These results indicate a novel molecular mechanism of the regulation of Notch signal, and also that defects in Crumbs might be involved in similar abnormal gamma-Secretase complex activity observed in Alzheimer's disease [4].

High impact information on crb

• The authors propose that a component of the apical Crumbs complex regulates the phosphorylation of the Frizzled (Fz) PCP receptor, thus modulating PCP in the Drosophila eye [5].
• HKB controls polarized cell shape change and apical membrane growth during salivary cell invagination via two downstream target genes, crumbs (crb), a determinant of the apical membrane, and klarsicht (klar), which mediates microtubule-dependent organelle transport [6].
• The similarity to CRB suggests a role for CRB1 in cell-cell interaction and possibly in the maintenance of cell polarity in the retina [7].
• crumbs encodes an EGF-like protein expressed on apical membranes of Drosophila epithelial cells and required for organization of epithelia [8].
• Drosophila Crumbs is required to maintain zonula adherens integrity during the rapid apical membrane expansion that builds the rhabdomere [9].

Biological context of crb

• This phosphorylation of Crumbs is functionally significant [10].
• Interaction of Par-6 and Crumbs complexes is essential for photoreceptor morphogenesis in Drosophila [11].
• Despite regaining cell polarity, however, epithelial cells in crb and lgl pathway mutants fail to re-establish normal overall tissue architecture, indicating that the timely acquisition of polarized cell structure is essential for normal tissue organization [12].
• Loss of Sdt causes strong defects in stalk membrane and rhabdomere resembling crb mutant phenotype [13].
• Part of a cross-hybridizing cDNA clone, derived from a gene located at position 95F on the third chromosome, was sequenced and found to encode five repeats with homology to those encoded by N and Dl [14].

Anatomical context of crb

• In Drosophila, the discovery of a gene, crb, controlling the coalescence of the spots of zonula adherens (ZA) into a adhesive ring around the cells was a major step [15].
• Role of the Crumbs complex in the regulation of junction formation in Drosophila and mammalian epithelial cells [15].
• In vivo analysis performed in cell cultures and in the Drosophila embryo show that the cytoplasmic domain of Crumbs can recruit DmPar-6 and DaPKC to the plasma membrane [16].
• Moreover, we use mosaic analysis to show that Crumbs (Crb) is required for the formation and maintenance of the follicular epithelium [17].
• Preliminary evidence on the spatial pattern of transcription indicates that the gene at position 95F is regulated in its expression, as it is transcribed in all ectodermal derivatives, with the exception of the central nervous system [14].

Associations of crb with chemical compounds

• Drosophila Stardust interacts with Crumbs to control polarity of epithelia but not neuroblasts [18].
• However, for the subset of ectodermal cells that delaminate and form neuroblasts, their polarity requires the function of Bazooka, but not of Stardust or Crumbs [18].
• Our data indicate that it is specifically the 4.1 protein/ezrin/radixin/moesin (FERM) domain binding consensus, and in particular, an arginine at position 7 in the cytoplasmic tail of Crumbs that is essential to efficiently recruit both the apical SBMS and the FERM domain protein, DMoesin [19].

Physical interactions of crb

• Here we show by in vitro analysis that, similar as in vertebrates, the single PDZ domain of Drosophila DmPar-6 can bind to the four C-terminal amino acids (ERLI) of the transmembrane protein Crumbs [16].
• We propose that Crumbs stabilizes the apical SBMS via DMoesin and actin, leading to reinforcement of the ZA and effectively coupling epithelial morphogenesis and cell polarity [19].

Co-localisations of crb

• Stardust colocalizes with Crumbs at the apicolateral boundary, although their expression patterns in sensory organs differ [18].

Regulatory relationships of crb

• Moreover, the phenotypic effect of overexpressing wild-type Crumbs is suppressed by reducing DaPKC activity [10].

Other interactions of crb

• Future work will help to understand several aspects of the Crumbs complex that are still unknown, like the role of the large extracellular domain or the precise function of Sdt and Dlt in the building of the ZA [15].
• In invaginating salivary cells, crb and klar mediate growth and delivery of apical membrane, respectively, thus regulating the size and shape of the salivary tube [6].
• DaPKC-dependent phosphorylation of Crumbs is required for epithelial cell polarity in Drosophila [10].
• Consistent with this hypothesis, we report that Crumbs is necessary for the organization of the apical SBMS in embryos and Schneider 2 cells, whereas the localization of Crumbs is not affected in karst mutants that eliminate the apical SBMS [19].
• Drosophila Stardust is a partner of Crumbs in the control of epithelial cell polarity [20].

Analytical, diagnostic and therapeutic context of crb

• Overexpression of Crumbs causes premature cell constriction in the amnioserosa, and dorsal closure defects are seen in embryos homozygous for hypomorphic crumbs alleles [21].
• Using immunoelectron microscopy it is shown that Crumbs is not a component of the ZA but is distributed over the entire apical cell surface and concentrated in the immediate vicinity of the ZA [22].

References