800 Facets of Retinal Degeneration

Cook, Tiffany; Zelhof, Andrew C.; Mishra, Monalisa; Nie, Jing

doi:10.1016/b978-0-12-384878-9.00008-x

Cited by 15 publications

(11 citation statements)

References 185 publications

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“…These fundamental differences have led to the idea that these photoreceptors are not evolutionarily related and instead, arose through independent mechanisms. However, it is also clear that many of the same factors are commonly used for the morphogenesis and function of both photoreceptor cell types, including Crumbs/CRB1, Spacemaker/EYS, Prominin, and Rhodopsin (see review by Cook et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Many genes required for photoreceptor differentiation in humans have homologous gene products in Drosophila . Moreover, mutations in several of these highly conserved genes result in retinal degeneration, both in flies and humans (Cook and Zelhof, 2008; Cook et al, 2011). Thus, Drosophila is becoming a powerful model for defining how retinal genes function in normal and pathologic photoreceptor physiology.…”

Section: Introductionmentioning

confidence: 99%

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OTX2 and CRX rescue overlapping and photoreceptor‐specific functions in the Drosophila eye

Terrell

Xie

Workman

et al. 2011

Developmental Dynamics

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Background Otd-related transcription factors are evolutionarily conserved to control anterior patterning and neurogenesis. In humans, two such factors, OTX2 and CRX, are expressed in all photoreceptors from early specification through adulthood and associate with several photoreceptor-specific retinopathies. It is not well understood how these factors function independently vs. redundantly, or how specific mutations lead to different disease outcomes. It is also unclear how OTX1 and OTX2 functionally overlap during other aspects of neurogenesis and ocular development. Drosophila encodes a single Otd factor that has multiple functions during eye development. Using the Drosophila eye as a model, we tested the ability of the human OTX1, OTX2, and CRX genes, as well as several disease-associated CRX alleles, to rescue the different functions of Otd. Results Our results indicate the following: OTX2 and CRX display overlapping, yet distinct subfunctions of Otd during photoreceptor differentiation; CRX disease alleles can be functionally distinguished based on their rescue properties; and all three factors are able to rescue rhabdomeric photoreceptor morphogenesis. Conclusions Our findings have important implications for understanding how Otx proteins have subfunctionalized during evolution, and cement Drosophila as an effective tool to unravel the molecular bases of photoreceptor pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

OTX2 and CRX rescue overlapping and photoreceptor‐specific functions in the Drosophila eye

Terrell

Xie

Workman

et al. 2011

Developmental Dynamics

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“…In addition, the fruit fly Drosophila has emerged as a valuable model for studying genetic and molecular mechanisms of retinal neurodegenerative diseases (reviewed in Wang and Montell, 2007; Knust, 2007; Cook et al, 2011). Using this model, Mendes and colleagues showed that, instead of inducing apoptosis, mild ER stress protects photoreceptor cells against cell death from various stimuli (Mendes et al, 2009).…”

Section: Er Stress and Retinal Degenerationmentioning

confidence: 99%

Endoplasmic reticulum stress and the unfolded protein responses in retinal degeneration

Zhang

Sanders

Fliesler

et al. 2014

Experimental Eye Research

116

107

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The endoplasmic reticulum (ER) is the primary intracellular organelle responsible for protein and lipid biosynthesis, protein folding and trafficking, calcium homeostasis, and several other vital processes in cell physiology. Disturbance in ER function results in ER stress and subsequent activation of the unfolded protein response (UPR). The UPR up-regulates ER chaperones, reduces protein translation, and promotes clearance of cytotoxic misfolded proteins to restore ER homeostasis. If this vital process fails, the cell will be signaled to enter apoptosis, resulting in cell death. Sustained ER stress also can trigger an inflammatory response and exacerbate oxidative stress, both of which contribute synergistically to tissue damage. Studies performed over the past decade have implicated ER stress in a broad range of human diseases, including neurodegenerative diseases, cancer, diabetes, and vascular disorders. Several of these diseases also entail retinal dysfunction and degeneration caused by injury to retinal neurons and/or to the blood vessels that supply retinal cells with nutrients, trophic and homeostatic factors, oxygen, and other essential molecules, as well as serving as a conduit for removal of waste products and potentially toxic substances from the retina. Collectively, such injuries represent the leading cause of blindness world-wide in all age groups. Herein, we summarize recent progress on the study of ER stress and UPR signaling in retinal biology and discuss the molecular mechanisms and the potential clinical applications of targeting ER stress as a new therapeutic approach to prevent and treat neuronal degeneration in the retina.

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“…While some such studies involve genes that were identified through their association with human disease (Lu and Vogel, 2009), many neurodegeneration-linked genes were originally discovered in the fly through forward genetic screens for adult lethality, retinal defects, or neurodegeneration itself (Cook et al, 2011; Knust, 2007; Kretzschmar, 2009; Min and Benzer, 1997). The very first adult lethal mutation connected to neurodegeneration, reported by Benzer and coworkers, was in the gene drd (Benzer, 1971).…”

Section: Introductionmentioning

confidence: 99%

Developmental expression of drop-dead is required for early adult survival and normal body mass in Drosophila melanogaster

Sansone

Blumenthal

2012

Insect Biochemistry and Molecular Biology

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In Drosophila melanogaster, mutations in the gene drop-dead (drd) result in early adult lethality, with flies dying within 2 weeks of eclosion. Additional phenotypes include neurodegeneration, tracheal defects, starvation, reduced body mass, and female sterility. The cause of early lethality and the function of the drd protein remain unknown. In the current study, the temporal profiles of drd expression required for adult survival and body mass regulation were investigated. Knockdown of drd expression by UAS-RNAi transgenes and rescue of drd expression on a drd mutant background by a UAS-drd transgene were controlled with the Heat Shock Protein 70 (Hsp70)-Gal4 driver. Flies were heat-shocked at different stages of their lifecycle, and the survival and body mass of the resulting adult flies were assayed. Surprisingly, the adult lethal phenotype did not depend upon drd expression in the adult. Rather, expression of drd during the second half of metamorphosis was both necessary and sufficient to prevent rapid adult mortality. In contrast, the attainment of normal adult body mass required a different temporal pattern of drd expression. In this case, manipulation of drd expression solely during larval development or metamorphosis had no effect on body mass, while knockdown or rescue of drd expression during all of pre-adult (embryonic, larval, and pupal) development did significantly alter body mass. Together, these results indicate that the adult-lethal gene drd is required only during development. Furthermore, the mutant phenotypes of body mass and lifespan are separable phenotypes arising from an absence of drd expression at different developmental stages.

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800 Facets of Retinal Degeneration

Cited by 15 publications

References 185 publications

OTX2 and CRX rescue overlapping and photoreceptor‐specific functions in the Drosophila eye

OTX2 and CRX rescue overlapping and photoreceptor‐specific functions in the Drosophila eye

Endoplasmic reticulum stress and the unfolded protein responses in retinal degeneration

Developmental expression of drop-dead is required for early adult survival and normal body mass in Drosophila melanogaster

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