Rescue of Photoreceptor Degeneration in Rhodopsin-Null
            <i>Drosophila</i>
            Mutants by Activated Rac1

Chang, Hui-Yun; Ready, Donald F.

doi:10.1126/science.290.5498.1978

Cited by 110 publications

(87 citation statements)

References 21 publications

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“…This targeting of Rh1 is essential for visual phototransduction but also for photoreceptor development (31). During the latter process, Rh1 plays an important role for the formation of a rhabdomere terminal web (RTW), an actin-based cytoskeletal scaffold (32). A direct involvement of NinaB for Rh1 maturation is supported by our in vivo analysis.…”

Section: Discussionsupporting

confidence: 54%

NinaB combines carotenoid oxygenase and retinoid isomerase activity in a single polypeptide

Oberhauser

Voolstra

Bangert

et al. 2008

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

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In animals, successful production of the visual chromophore (11-cis-retinal or derivatives thereof such as 11-cis-3-hydroxy-retinal) is essential for photoreceptor cell function and survival. These carotenoid-derived compounds must combine with a protein moiety (the opsin) to establish functional visual pigments. Evidence from cell culture systems has implicated that the retinal pigment epithelium protein of 65 kDa (RPE65) is the long-sought all-trans to 11-cis retinoid isomerase. RPE65 is structurally related to nonheme iron oxygenases that catalyze the conversion of carotenoids into retinoids. In vertebrate genomes, two carotenoid oxygenases and RPE65 are encoded, whereas in insect genomes only a single representative of this protein family, named NinaB (denoting neither inactivation nor afterpotential mutant B), is encoded. We here cloned and functionally characterized the ninaB gene from the great wax moth Galleria mellonella. We show that the recombinant purified enzyme combines isomerase and oxygenase (isomerooxygenase) activity in a single polypeptide. From kinetics and isomeric composition of cleavage products of asymmetrical carotenoid substrates, we propose a model for the spatial arrangement between substrate and enzyme. In Drosophila, we show that carotenoid-isomerooxygenase activity of NinaB is more generally found in insects, and we provide physiological evidence that carotenoids such as 11-cis-retinal can promote visual pigment biogenesis in the dark. Our study demonstrates that trans/cis isomerase activity can be intrinsic to this class of proteins and establishes these enzymes as key components for both invertebrate and vertebrate vision. RPE65 ͉ vision ͉ visual chromophoreA nimal visual pigments (rhodopsins) are bipartite G-proteincoupled receptors consisting of an opsin moiety and a carotenoid-derived retinylidene chromophore (1). Two fundamental issues in the pathway for visual chromophore production have resisted molecular analysis for a long time: first, the oxidative cleavage of C 40 carotenoids into C 20 retinoids; and second, the all-trans to 11-cis isomerization of retinoids.The molecular basis for the oxidative cleavage was resolved by cloning and characterization of NinaB (denoting neither inactivation nor afterpotential mutant B), which converts carotenoids into retinoids in Drosophila melanogaster (2, 3). Thereafter, several related carotenoid-15,15Ј-oxygenases (CMO1) have been identified and characterized in vertebrates including human beings (4-7). In addition, in vertebrates a second type of carotenoid-oxygenase, carotenoid-9Ј,10Ј-monooxygenase (CMO2) has been identified that cleaves carotenoids asymmetrically (8, 9), although its physiological function is not yet fully understood.The isomerization problem concerns the questions of how the visual chromophore is produced to establish functional visual pigments and, in vertebrates, how the all-trans visual photoproduct is isomerized back to the 11-cis chromophore, to maintain visual responsiveness. Recently, evidence in cell cultur...

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Section: Discussionsupporting

confidence: 54%

NinaB combines carotenoid oxygenase and retinoid isomerase activity in a single polypeptide

Oberhauser

Voolstra

Bangert

et al. 2008

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

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“…Their position is not so deep into the brain, with reference to the CRY-containing lateral neurons (Emery et al 2000b). The dorsally located neurons could possess an opsin that does not need the norpA-encoded enzyme for the photransduction process in question (Chang and Reddy 2000).…”

Section: Discussionmentioning

confidence: 99%

Rhythm Defects Caused by Newly Engineered Null Mutations in Drosophila's cryptochrome Gene

Doleželová¹,

Doležel²,

2007

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Much of the knowledge about cryptochrome function in Drosophila stems from analyzing the cry b mutant. Several features of this variant's light responsiveness imply either that CRY b retains circadianphotoreceptive capacities or that additional CRY-independent light-input routes subserve these processes. Potentially to resolve these issues, we generated cry knock-out mutants (cry 0 's) by gene replacement. They behaved in an anomalously rhythmic manner in constant light (LL). However, cry 0 flies frequently exhibited two separate circadian components in LL, not observed in most previous cry b analyses. Temperature-dependent circadian phenotypes exhibited by cry 0 flies suggest that CRY is involved in core pacemaking. Further locomotor experiments combined cry 0 with an externally blinding mutation (norpA P24 ), which caused the most severe decrements of circadian photoreception observed so far. cry b cultures were shown previously to exhibit either aperiodic or rhythmic eclosion in separate studies. We found cry 0 to eclose in a solidly periodic manner in light:dark cycles or constant darkness. Furthermore, both cry 0 and cry b eclosed rhythmically in LL. These findings indicate that the novel cry 0 type causes more profound defects than does the cry b mutation, implying that CRY b retains residual activity. Because some norpA P24 cry 0 individuals can resynchronize to novel photic regimes, an as-yet undetermined light-input route exists in Drosophila.

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“…Interestingly, transgenic expression of a dominant active Rac, the small Rho GTPase involved in the formation of the actin cytoskeleton, prevents retinal degeneration in ninaE I17 flies. 102 Therefore defects in rhabdomere expansion can be overcome by the active elongation of the actin cytoskeleton. Retinal degeneration in ninaE also can be rescued by vitamin A deprivation, suggesting that accumulation of free retinal is toxic to photoreceptors.…”

Section: Cell Death Caused By Recessive Nina Mutationsmentioning

confidence: 99%

Molecular genetics of retinal degeneration: A Drosophila perspective

Shieh

2011

fly

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Rescue of Photoreceptor Degeneration in Rhodopsin-Null Drosophila Mutants by Activated Rac1

Cited by 110 publications

References 21 publications

NinaB combines carotenoid oxygenase and retinoid isomerase activity in a single polypeptide

NinaB combines carotenoid oxygenase and retinoid isomerase activity in a single polypeptide

Rhythm Defects Caused by Newly Engineered Null Mutations in Drosophila's cryptochrome Gene

Molecular genetics of retinal degeneration: A Drosophila perspective

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