Depleting Rac1 in mouse rod photoreceptors protects them from photo-oxidative stress without affecting their structure or function.
In nonphagocytic cells, Rac1 is a component of NADPH oxidase that produces reactive oxygen species [Ushio-Fukai M (2006) Sci STKE 2006:re8]. Rac1 is expressed abundantly in mammalian retinal photoreceptors, where it is activated in response to light stimuli [Balasubramanian N, Slepak VZ (2003) Curr Biol 13:1306-1310]. We used Cre-LoxP conditional gene targeting to knock down Rac1 expression in mouse rod photoreceptors and found protection against light-induced photoreceptor death compared with WT litter-mates. We also found a similar protective effect on rods using apocynin, which inhibits NADPH oxidase activity. These results implicate both neuronal Rac1 and NADPH oxidase in cell death in this model of CNS degeneration. Studies in which dominant-mutants of Rac1 were expressed in transgenic Drosophila species demonstrated that Rac1 is a key regulator of photoreceptor morphogenesis and polarity [Chang HY, Ready DF (2000) Science 290:1978-1980]. However, we found that diminished Rac1 expression in mouse rods had no effect on retinal structure or function examined by light microscopy, electron microscopy, rhodopsin measurement, electroretinogram activity, and visual acuity, indicating rod outer segment morphogenesis proceeded normally in Rac1 conditional knockout mice. The lack of structural or functional effect of Rac1 depletion on photoreceptors, but protection under conditions of stress, indicate that the Rac1 pathway warrants exploration as a target for therapy in retinal neurodegenerative diseases.
Haruta
Masatoshi
M
National Institute on Deafness and Other Communication Disorders and National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Bush
Ronald A
RA
Kjellstrom
Sten
S
Vijayasarathy
Camasamudram
C
Zeng
Yong
Y
Le
Yun-Zheng
YZ
Sieving
Paul A
PA
D000818:Animals; D008027:Light; D051379:Mice; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D018384:Oxidative Stress; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
D009479:Neuropeptides; C484602:Rac1 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein