Morphological Defects in ora<sup>jk84</sup>Photoreceptors Caused by Mutation in R1-6 Opsin Gene of Drosophila

O'Tousa, Joseph E.; Leonard, Debra S.; Pak, William L.

doi:10.3109/01677068909107099

Cited by 91 publications

(73 citation statements)

References 19 publications

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“…In ninaE I17 mutants, the RTW is not organized during morphogenesis and thus photoreceptors have improperly formed rhabdomeres (8). In addition, in 3-dayold flies, rhabdomeric elements involute into the photoreceptors and are subsequently removed slowly (7,9,10). Here, we demonstrate that expression of ceramidase clears ninaE I17 mutant photoreceptors of these involuting rhabdomeric membranes.…”

mentioning

confidence: 75%

Ceramidase expression facilitates membrane turnover and endocytosis of rhodopsin in photoreceptors

Acharya

Mowen²,

Nagashima³

et al. 2004

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

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Transgenic expression of ceramidase suppresses retinal degeneration in Drosophila arrestin and phospholipase C mutants. Here, we show that expression of ceramidase facilitates the dissolution of incompletely formed and inappropriately located elements of rhabdomeric membranes in ninaE I17 mutants lacking the G protein receptor Rh1 in R1-R6 photoreceptor cells. Ceramidase expression facilitates the endocytic turnover of Rh1. Although ceramidase expression aids the removal of internalized rhodopsin, it does not affect the turnover of Rh1 in photoreceptors maintained in dark, where Rh1 is not activated and thus has a slower turnover and a long half-life. Therefore, the phenotypic consequence of ceramidase expression in photoreceptors is caused by facilitation of endocytosis. This study provides mechanistic insight into the sphingolipid biosynthetic pathway-mediated modulation of endocytosis and suppression of retinal degeneration.S phingolipids are integral components of eukaryotic cell membranes. They are essential for survival of yeast, Drosophila, and mammals. Sphingolipids have a hydrophobic backbone moiety, ceramide, linked to a variable polar head group, e.g., phosphorylcholine in sphingomyelin and a saccharide in glycosphingolipids. Ceramide itself consists of a long chain base linked to a fatty acid. Ceramide, sphingosine, and sphingosine-1-P are lipid second messengers modulating a variety of cellular functions (1-3). Ceramide is at the branch point of the sphingolipid biosynthetic pathway and serves as a substrate for several enzymes, e.g., sphingomyelin synthase, ceramidase, ceramide kinase, and glucosylceramide synthase. In Drosophila, transgenic expression of a neutral ceramidase is accompanied by a decrease in the levels of ceramide (4). We have shown that modulation of enzymes of the sphingolipid biosynthetic pathway suppressed retinal degeneration in certain phototransduction mutants (4). Transgenic expression of ceramidase or a loss of one copy of the rate-limiting enzyme in the sphingolipid biosynthetic pathway, namely, Serine Palmitoyl CoA transferase, suppressed retinal degeneration in arrestin and phospholipase C (norpA) mutants. These backgrounds also suppressed degeneration in a dynamin mutant, suggesting that ceramidase was modulating the endocytic pathway. To gain further insight into the mechanism of ceramidase action, we have investigated the effects of ceramidase expression in the rhodopsin null mutant, ninaE I17 . Rhodopsin, the G protein-coupled receptor, transduces light signal in Drosophila photoreceptors R1-R6 (5, 6). Rhodopsin is also involved in the formation of a rhabdomere terminal web (RTW), an actin-based cytoskeletal scaffold implicated in rhabdomere biogenesis (7,8). Rhabdomeres are densely organized, specialized areas of plasma membrane that house the signal transduction machinery of photoreceptors. In ninaE I17 mutants, the RTW is not organized during morphogenesis and thus photoreceptors have improperly formed rhabdomeres (8). In addition, in 3-dayold flies, rhabdomeric e...

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mentioning

confidence: 75%

Ceramidase expression facilitates membrane turnover and endocytosis of rhodopsin in photoreceptors

Acharya

Mowen²,

Nagashima³

et al. 2004

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

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“…*Highest concentration of nodulisporic acid tested. mapped further by in situ hybridization to deficiency chromosomes DfB16 and Df12 (11). The DmGluCl␣ probe hybridized to DfB16 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Fly food containing insecticides was made with Instant Drosophila medium, formula 4-24 (Carolina Biological Supply), to which a mixture of water and insecticide dissolved in DMSO was added. The following Drosophila strains were used: wild-type Oregon-R, Or-R; white eyed wild-type, w; Resistance to dieldrin, Rdl MD-RR (A302S); a second and third chromosome balancer, SM6aCyO; TM6B, Tb͞ap xa ; a second chromosome balancer, SM6b, CyO͞Sp J L Pin; a third chromosome balancer, TM3,Ser e͞TM6B,Tb e (all provided by the Bloomington Drosophila Stock Center, Bloomington, IN); a glc deficiency line Df(3R)ora 12 ͞TM6, Ubx, referred to as Df12, which contains breakpoints 92A6:92D2; a deficiency line Df(3R) ora B16 adjacent to Df12, referred to as DfB16, which contains breakpoints 92A12-92B1; and 92E10-92E15 (11,12). glc 1 , derived from Or-R by nodulisporic acid selection pressure, refers to nodulisporic acid-and ivermectin-resistant glc 1 ͞glc 1 .…”

Section: Methodsmentioning

confidence: 99%

Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin

Kane

Hirschberg

Qian

et al. 2000

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

174

146

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The fruit fly Drosophila melanogaster was used to examine the mode of action of the novel insecticide and acaricide nodulisporic acid. Flies resistant to nodulisporic acid were selected by stepwise increasing the dose of drug in the culture media. The resistant strain, glc 1 , is at least 20-fold resistant to nodulisporic acid and 3-fold cross-resistant to the parasiticide ivermectin, and exhibited decreased brood size, decreased locomotion, and bang sensitivity. Binding assays using glc 1 head membranes showed a marked decrease in the affinity for nodulisporic acid and ivermectin. A combination of genetics and sequencing identified a proline to serine mutation (P299S) in the gene coding for the glutamategated chloride channel subunit DmGluCl␣. To examine the effect of this mutation on the biophysical properties of DmGluCl␣ channels, it was introduced into a recombinant DmGluCl␣, and RNA encoding wild-type and mutant subunits was injected into Xenopus oocytes. Nodulisporic acid directly activated wild-type and mutant DmGluCl␣ channels. However, mutant channels were Ϸ10-fold less sensitive to activation by nodulisporic acid, as well as ivermectin and the endogenous ligand glutamate, providing direct evidence that nodulisporic acid and ivermectin act on DmGluCl␣ channels.

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“…The first mutations linked to retinal degeneration were in ninaE, which encode the major rhodopsin, Rh1 [40,41,207,208]. This observation turned out to have relevance to human retinal dystrophies, as mutations in human rhodopsin were shown subsequently to account for a large proportion of the cases of autosomal dominant retinitis pigmentosa disease (ADRP) [209][210][211][212][213].…”

Section: Retinal Degenerationmentioning

confidence: 99%

“…Since Rh1 plays a structural role in photoreceptor cells [214], in addition to functioning as a light-receptor, most loss-of-function ninaE alleles result in light-independent retinal degeneration [208,215]. The degeneration in ninaE is not dependent on the signal transduction cascade as the severity of photoreceptor cell death mutation is not reduced by disruption of the PLC (NORPA), which is required for phototransduction [215,216].…”

Section: Retinal Degenerationmentioning

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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Morphological Defects in ora^jk84Photoreceptors Caused by Mutation in R1-6 Opsin Gene of Drosophila

Cited by 91 publications

References 19 publications

Ceramidase expression facilitates membrane turnover and endocytosis of rhodopsin in photoreceptors

Ceramidase expression facilitates membrane turnover and endocytosis of rhodopsin in photoreceptors

Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin

Phototransduction and retinal degeneration in Drosophila

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Morphological Defects in orajk84Photoreceptors Caused by Mutation in R1-6 Opsin Gene of Drosophila

Cited by 91 publications

References 19 publications

Ceramidase expression facilitates membrane turnover and endocytosis of rhodopsin in photoreceptors

Ceramidase expression facilitates membrane turnover and endocytosis of rhodopsin in photoreceptors

Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin

Phototransduction and retinal degeneration in Drosophila

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Morphological Defects in ora^jk84Photoreceptors Caused by Mutation in R1-6 Opsin Gene of Drosophila