Drosophila Crumbs Is Required to Inhibit Light-Induced Photoreceptor Degeneration

Johnson, Kevin M.; Grawe, Ferdi; Grzeschik, Nicola A.; Knust, Elisabeth

doi:10.1016/s0960-9822(02)01180-6

Cited by 130 publications

(202 citation statements)

References 28 publications

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“…Experiments on fruit fly Crumbs showed that the extracellular domain played an important role in prevention against light damage (Johnson et al, 2002). Here, we show that the amino acid substitution in Crb1 C249W caused loss of protection against the effects of light (increased incidence of retinal folds and upregulation of GFAP at foci, and low levels of retinal Pttg1 transcripts).…”

Section: Crb1mentioning

confidence: 61%

A Single Amino Acid Substitution (Cys249Trp) in Crb1 Causes Retinal Degeneration and Deregulates Expression of Pituitary Tumor Transforming GenePttg1

Pavert¹,

Meuleman²,

Malysheva³

et al. 2007

J. Neurosci.

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Different mutations in the human Crumbs homolog-1 (CRB1) gene cause a variety of retinal dystrophies, such as Leber congenital amaurosis, early onset retinitis pigmentosa (e.g., RP12), RP with Coats-like exudative vasculopathy, and pigmented paravenous retinochoroidal atrophy. Loss of Crb1 leads to displaced photoreceptors and focal degeneration of all neural layers attributable to loss of adhesion between photoreceptors and Müller glia cells. To gain insight into genotype-phenotype relationship, we generated Crb1 C249W mice that harbor an amino acid substitution (Cys249Trp) in the extracellular sixth calcium-binding epidermal growth factor domain of Crb1. Our analysis showed that Crb1 C249W as wild-type protein trafficked to the subapical region adjacent to adherens junctions at the outer limiting membrane (OLM). Hence, these data suggest correct trafficking of the corresponding mutant CRB1 in RP12 patients. Crb1C249W mice showed loss of photoreceptors in the retina, relatively late compared with mice lacking Crb1. Scanning laser ophthalmoscopy revealed autofluorescent dots that presumably represent layer abnormalities after OLM disturbance. Gene expression analyses revealed lower levels of pituitary tumor transforming gene 1 (Pttg1) transcripts in Crb1 C249W/؊ knock-in and Crb1 ؊/؊ knock-out compared with control retinas. Exposure to white light decreased levels of Pttg1 in Crb1 mutant retinas. We hypothesize deregulation of Pttg1 expression attributable to a C249W substitution in the extracellular domain of Crb1.

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Section: Crb1mentioning

confidence: 61%

A Single Amino Acid Substitution (Cys249Trp) in Crb1 Causes Retinal Degeneration and Deregulates Expression of Pituitary Tumor Transforming GenePttg1

Pavert¹,

Meuleman²,

Malysheva³

et al. 2007

J. Neurosci.

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“…In addition, human homologues of Crb are implicated in retinitis pigmentosa and Leber congenital amaurosis, two heritable forms of human disease of photoreceptor degeneration (21)(22)(23)(24). In Drosophila, crb photoreceptors also degenerate under intense lighting conditions (25), resembling the phenotype in human diseases. It would be of interest to find out whether mutations in the human homologues of Sdt, Dlt, and possibly aPKC lead to photoreceptor degeneration.…”

Section: Discussionmentioning

confidence: 95%

Distinct roles of Bazooka and Stardust in the specification of Drosophila photoreceptor membrane architecture

Hong

Ackerman

Jan

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Photoreceptors form during Drosophila pupal development and acquire elaborate membrane structures, including the rhabdomeres and stalk membranes. Here, we show that the development of these cellular structures involves two distinct processes: the establishment of apical-basal polarity that requires Bazooka (Baz), and the regionalization of apical membrane into stalk membranes and rhabdomeres that requires Stardust (Sdt). In the absence of Baz, the apical-basal polarity is compromised in early pupal photoreceptors, and no identifiable apical membrane domain is formed. Sdt, in contrast, plays a more limited role in apical-basal polarity but is essential for the proper localization of transmembrane protein Crumbs (Crb), known to be required in the biogenesis of stalk membrane. Loss of Sdt causes strong defects in stalk membrane and rhabdomere resembling crb mutant phenotype. Thus, proteins required for establishing the early embryonic epithelial polarity are used later for the morphogenesis of photoreceptors, with Baz and Sdt functioning in different aspects of the formation of the apical-basal cellular architecture. D ifferent cell types exhibit different degrees of complexity in their morphogenesis. Epithelial cells are polarized to have distinct apical versus basolateral domains. Cascades of protein complexes have been found to specify this polarity (1). Many cells that are derived from epithelial cells have more complex morphology to carry out important functions, such as photoreceptors for vision. How these cells elaborate their different membrane domains is not well understood. In Drosophila, photoreceptors have clearly recognizable apical-basal polarity demarcated by zonula adherens (ZA) (2). Is this polarity established by the same protein complexes that specify epithelial polarity? How might this apical-basal polarity specification influence other structural specializations, e.g., the elaboration of rhabdomere perpendicular to the apical-basal axis? And, what are the mechanisms for regionalizing specific membrane domains in conjunction with the polarity?One approach to address these questions in Drosophila is to test whether similar organizations of genetic pathways in simple and relatively well studied embryonic epithelial polarity also underlie the development of polarity in more specialized cell types like photoreceptors. Drosophila embryonic epithelium represents one of the simplest polarized cell types, and its apical-basal polarity is controlled largely in concert by three protein complexes (1). Baz(DmPar-3)͞DmPar-6͞DaPKC (atypical protein kinase C) plays the earliest and essential role in initiating the apical-basal polarity, whereas Sdt͞Crb͞Dlt (Discs lost) maintains the ZA formation and polarity by counteracting the activity of Dlg (Discs large)͞Lgl (Lethal giant larvae)͞Scrib (Scribble) (3, 4). Except for DaPKC, Crumbs (Crb), and Lgl, all of these proteins contain one or more PDZ domains important for mediating protein-protein interactions (1). The first insight that at least some of these protei...

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“…This issue may have bearing on human retinal dystrophies as the phenomenon of retinal degeneration resulting from stable rhodopsin/arrestin complexes has been documented in rodent animal models [236,237]. Mutations in Drosophila crumbs and its human homolog lead to light-induced retinal degeneration, but the mechanisms underlying these retinal degenerations are poorly understood [238,239]. The Drosophila retinal pigment cells appear to function similarly to human RPE cells in the generation of the chromophore [81], and many genetic defects in human RPE cells are known to cause photoreceptor cell degeneration.…”

Section: Discussionmentioning

confidence: 99%

Phototransduction and retinal degeneration in Drosophila

Wang

Montell

2007

Pflugers Arch - Eur J Physiol

261

303

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Drosophila visual transduction is the fastest known G-protein-coupled signaling cascade and has therefore served as a genetically tractable animal model for characterizing rapid responses to sensory stimulation. Mutations in over 30 genes have been identified, which affect activation, adaptation, or termination of the photoresponse. Based on analyses of these genes, a model for phototransduction has emerged, which involves phosphoinoside signaling and culminates with opening of the TRP and TRPL cation channels. Many of the proteins that function in phototransduction are coupled to the PDZ containing scaffold protein INAD and form a supramolecular signaling complex, the signalplex. Arrestin, TRPL, and Gα q undergo dynamic light-dependent trafficking, and these movements function in long-term adaptation. Other proteins play important roles either in the formation or maturation of rhodopsin, or in regeneration of phosphatidylinositol 4,5-bisphosphate (PIP 2 ), which is required for the photoresponse. Mutation of nearly any gene that functions in the photoresponse results in retinal degeneration. The underlying bases of photoreceptor cell death are diverse and involve mechanisms such as excessive endocytosis of rhodopsin due to stable rhodopsin/arrestin complexes and abnormally low or high levels of Ca 2+ . Drosophila visual transduction appears to have particular relevance to the cascade in the intrinsically photosensitive retinal ganglion cells in mammals, as the photoresponse in these latter cells appears to operate through a remarkably similar mechanism.

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Drosophila Crumbs Is Required to Inhibit Light-Induced Photoreceptor Degeneration

Cited by 130 publications

References 28 publications

A Single Amino Acid Substitution (Cys249Trp) in Crb1 Causes Retinal Degeneration and Deregulates Expression of Pituitary Tumor Transforming GenePttg1

A Single Amino Acid Substitution (Cys249Trp) in Crb1 Causes Retinal Degeneration and Deregulates Expression of Pituitary Tumor Transforming GenePttg1

Distinct roles of Bazooka and Stardust in the specification of Drosophila photoreceptor membrane architecture

Phototransduction and retinal degeneration in Drosophila

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