Blocking apoptosis prevents blindness in Drosophila retinal degeneration mutants

Davidson, Florence F.; Steller, Hermann

doi:10.1038/35385

Cited by 147 publications

(97 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the diversity in mechanisms underlying photoreceptor cell death in Drosophila, many of the retinal degenerations show features of apoptosis, which is reminiscent of human retinal dystrophies [31,98,234,235]. Although a lot of progress has been made over the past few years, there remain many unanswered questions regarding the mechanisms of retinal degeneration in Drosophila.…”

Section: Discussionmentioning

confidence: 99%

Phototransduction and retinal degeneration in Drosophila

Wang

Montell

2007

Pflugers Arch - Eur J Physiol

261

303

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Phototransduction and retinal degeneration in Drosophila

Wang

Montell

2007

Pflugers Arch - Eur J Physiol

261

303

View full text Add to dashboard Cite

show abstract

“…It has previously been reported that the baculoviral caspase inhibitor, p35, was not only capable of preventing apoptosis in retinal degenerative Drosophila mutants, but also of maintaining visual functionality. 61 Interestingly, a recent report has attributed an anti-oxidant property to p35 62 suggesting that cell survival in these retinal degenerative mutants may not only require inhibition of the effectors of the cell death machinery, but also of the initiating signals. In light of this view, and as our findings demonstrate, the use of antioxidants may be of more therapeutic benefit in the prevention of retinal degeneration in RP than inhibitors of the caspases.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress induces caspase-independent retinal apoptosis in vitro

2000

View full text Add to dashboard Cite

Apoptosis is the mode of cell death in retinitis pigmentosa (RP), a heterogeneous group of retinal degenerations. The activation of the caspase proteases forms a pivotal step in the initiation and execution phase of apoptosis in many cells. Inhibition of caspases has been reported to prevent apoptosis in many model systems. However, we demonstrate the absence of caspase activation during retinal cell apoptosis in vitro which involves phosphatidylserine (PS) externalisation, DNA nicking and cell shrinkage. In addition, zVAD-fmk, DEVD-CHO and BD-fmk, inhibitors of the caspases, were unable to alter the characteristics or kinetics of apoptosis, implying that retinal cell death in vitro follows a caspase-independent pathway. We have previously demonstrated the ability of reactive oxygen species (ROS) to act as mediators of retinal cell apoptosis in vitro as well as the ability of antioxidants to prevent retinal cell apoptosis. Here we demonstrate the oxidative inactivation of caspases in this model of retinal apoptosis and provide evidence for an oxidative stress driven cell death pathway that does not involve caspase activity and which retains key features of apoptotic cell death. Furthermore, our data indicates that apoptotic events such as PS exposure, DNA nicking and cell shrinkage may occur independently of caspase activity. Cell Death and Differentiation (2000) 7, 282 ± 291.

show abstract

“…Nonetheless, p35 effectively inhibits a broad range of active caspases and can block cell death not only in insects, but also in C. elegans, vertebrates, and plants (Danon et al 2004;Izquierdo et al 1999;Xue and Horvitz 1995;Sugimoto et al 1994). In Drosophila, targeted expression of p35 blocks both naturally occurring developmental cell death as well as ectopic cell death induced by genetic or environmental means (Davidson and Steller 1998;Hay et al 1994).…”

mentioning

confidence: 99%

Targeted expression of p35 reveals a role for caspases in formation of the adult abdominal cuticle in Drosophila

Kester¹,

Nambu²

2011

Int. J. Dev. Biol.

View full text Add to dashboard Cite

Programmed cell death is a fundamental aspect of metazoan development associated with the elaboration of disparate tissues and structures. Specialized cysteine proteases, the caspases, are mediators of cell death; once activated they cleave substrate proteins to dismantle doomed cells. Caspase activity is regulated by several cellular and viral inhibitors. The baculovirus p35 protein blocks the action of a wide range of caspases and inhibits cell death in divergent species. Here, we utilize the Gal4/UAS system to target p35 expression and analyze the requirements of caspase activity for development in Drosophila. We confirm that cell death is essential for proper morphogenesis of the adult male external genitalia and distal portions of the legs. In addition, we find that caspases are also required for elimination of larval epidermal cells and normal elaboration of the adult abdominal cuticle by histoblast derivatives. In particular, rescued p35-expressing larval epidermal cells accumulate along the abdominal midline and are associated with corresponding splits in both dorsal and ventral cuticle structures. This study reveals a novel role for cell death in a specific morphogenetic processes.

show abstract

Blocking apoptosis prevents blindness in Drosophila retinal degeneration mutants

Cited by 147 publications

References 28 publications

Phototransduction and retinal degeneration in Drosophila

Phototransduction and retinal degeneration in Drosophila

Oxidative stress induces caspase-independent retinal apoptosis in vitro

Targeted expression of p35 reveals a role for caspases in formation of the adult abdominal cuticle in Drosophila

Contact Info

Product

Resources

About