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Marc Kantorow, Wanda Lee Kantorow, Lisa A. Brennan, Daniel Chauss, Amer Riazuddin, Ales Cvekl, James F. Hejtmancik; The Role of FYCO1 And Autophagy in Lens Defense, Differentiation And Cataract Formation. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1724.
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Mutation of the FYCO1 gene in humans causes autosomal recessive congenital cataract (Chen et al., AJHG, 2011) demonstrating that FYCO1 plays a significant role in lens function. FYCO1 has been implicated in the transport of autophagy components in non-lens cells. Here, we explored the role of FYCO1 and autophagy in lens function.
Autophagy markers (LC3 , LAMP2A and Rab7) and FYCO1 were identified to be highly expressed in mouse and human lenses and lens sub-components by western analysis. These were also localized in lens cells and lens cell organelles by confocal imaging and in embryonic mouse lenses and adult human lenses by immunohistochemistry. Autophagy was monitored in HLEB3 lens cells by cadaverin fluorescence and fluorescently-tagged LC3 accumulation following oxidative stress-, rapamycin, and/or tamoxifin treatment with or without chloroquine inhibition.
The autophagy markers LC3, LAMP2A, and Rab 7 are expressed in mouse and human lenses and lens cells. FYCO1 is expressed at high levels in the lens epithelium, bow region and embryonic fibers. FYCO1 also is localized intracellularly to autophagosomes, lysosomes and endosomes in cultured human lens epithelial cells. Autophagy occurred in lens cells in the absence of any treatment but was increased by tamoxifin, rapamycin and, importantly, oxidative stress treatment. Interestingly, inhibition of autophagy using chloroquine resulted in decreased lens cell viability.
Our results demonstrate that autophagy is an important process for lens cell function and is induced in lens cells upon oxidative stress treatment. The presence of high levels of FYCO1 in the bow region and embryonic nucleus suggest it plays a role in organelle breakdown during lens differentiation. These results suggest that FYCO1 and other autophagy components play important roles in lens cell maintenance, defense against oxidative and other insults, and differentiation.
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