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GL King; Identification of IRS2's Critical Role in Retinal Development and Degeneration in Transgenic Mice . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2715.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Insulin and IGF-1 can regulate retinal neovascularization but their effect on neural retina is unknown. Insulin and IGF-1 mediate many metabolic effects through intracellular signaling proteins, IRS1 + 2. We have made mice with deletion of either IRS1 (IRS1-/-) or IRS2 (IRS2-/-) and surprisingly, only IRS2-/- mice exhibited poor neural and vascular retinal development, which are now characterized. Method: IRS1-/- and IRS2-/- mice have been made in C57B/129 background. Apoptosis was measured by TUNEL assay and DNA synthesis by BrdU incorporation. IGF-1 actions were assessed by immunoblotting of IRS1, 2, caspases 3, Akt and their phosphorylated (activated) forms. VEGF mRNA was quantitated by RT-PCR. Results: IRS2-/- mice at 3 weeks of age had thinner retinas then IRS1-/- or wild type mice (¯ 35%). Morphometric analysis showed reduced number of cells in inner and outer nuclear and plexiforms layers. BrdU incorporation also showed a 35% reduction in retinal cells of IRS2-/- vs wild type. Retinal thickness decreased from 3-9 weeks of age which coincided with increases in apoptosis by TUNEL assay and caspases 3 level and decreases in IGF-1 stimulated Akt phosphorylation (¯ 50%). In contrast, no retinal abnormalities were observed in IRS1-/- mice. Chronic studies in IRS2-/- mice were too difficult since IRS2-/- mice developed severe diabetes after 9 weeks due to pancreatic atrophy. Thus, we overexpressed Pdx1, a pancreatic specific transcription factor for growth, to rescue pancreatic b-cells of IRS2-/- mice which prevented diabetes, but retained thinning of the retina. At 16 months IRS2-/- Pdx1 Tg mice exhibited either a few photoreceptor cells or total loss of outer nuclear layer. Neonatal IRS2-/- mice also had decreased expression of VEGF mRNA and capillary density at basal state. In the neonatal hyperoxia model, neovascularization was totally absent in response to hypoxia in the IRS2-/- mice and was partially (¯ 50%) reduced in the IRS1-/- mice. Conclusion: Thus, these data have identified IRS2 for the first time as a critical component in the development and degeneration of neural retina and retinal neovascularization in response to hypoxia.
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