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I. Ivanovic, Y. Z. Le, R. E. Anderson, R. V. Rajala; Deletion of the p85 Regulatory Subunit of Phosphoinositide 3-Kinase in Cone Photoreceptor Cells Results in Cone Photoreceptor Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5438.
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© ARVO (1962-2015); The Authors (2016-present)
Lipid products generated by phosphoinositide 3-kinase (PI3K) have been shown to mediate and regulate a variety of cellular events in the retina. Existing evidence shows the importance of PIs in retinal photoreceptor functions such as modulation of phototransduction, protein translocation, disk biogenesis, and cell survival. We have shown that illumination induces tyrosine phosphorylation of multiple retinal proteins, including the insulin receptor (IR). Association of the p85 regulatory subunit of PI3K with phosphotyrosine residues on the IR leads to the elevation of PI3K activity in rod outer segments. Genetic ablation of IR and IRS-2, which are both upstream effectors of PI3K, and ablation of Akt2 and Bcl-xl, which are both downstream effectors of PI3K, exacerbated light stress-induced rod photoreceptor degeneration. To investigate the role of PI3K in cones, we disrupted the PI3K gene specifically in mouse cone photoreceptors and determined the effect of its deletion on retinal structure and function.
We bred mice expressing cre-recombinase in cones to mice with a floxed p85 regulatory subunit of PI3K to generate offspring with a conditional deletion of PI3K enzymatic activity in cones. Cre recombinase expression and cone-specific localization was confirmed by Western blot and immunohistochemistry (IHC), respectively. Cone structural integrity was determined by IHC using M- and S-opsin specific antibodies. Electroretinography (ERG) was used to assess retinal rod and cone function at one and six months of age. The susceptibility of rods and cones to light-induced damage was determined in six-week-old pigmented transgenic and wild type litter mates by exposing them for 5 days at 7000 lux intensity. Functional changes were determined by ERG.
Cone opsin was normally expressed and localized in PI3K-/- mice. Pigmented PI3K-/- mice exhibited loss of cone function (approx. 30% loss) at six months of age. Light stress at six weeks of age caused a significant loss of cone function. The cone functional loss caused by light stress was equivalent (approx. 30% loss) to the cone functional loss observed in six-month-old PI3K-/- mice. In PI3K-/- mice both, the six-months-old and the light-stressed, rod functional loss was comparable to the control litter mates.
Our results provide the first evidence that cones utilize PI3K-mediated survival signals to protect themselves from stress-induced cell death.
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