Purchase this article with an account.
X. Yi, X. Dong, S. Guo, M.F. White; Transcription Factor FoxO1 Mediates the Survival of Photoreceptors . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4744.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Previously, we demonstrated that insulin receptor substrate 2 (Irs2)–branch insulin/IGF1 signaling is essential for the survival of photoreceptors. However, the mechanism underlying the protective role of insulin/IGF1 in photoreceptor is not clear yet. In this study, we examined the role of FoxO1, an important insulin/IGF1–regulated transcription factor, in the survival of photoreceptors.
Insulin/IGF1–induced activation of Akt, the phosphorylation, and degradation of FoxO1 in 661W cells (mouse photoreceptor cell line) were studied by Western blot. Signal transduction pathways mediating inactivation of FoxO1were characterized by the use of specific kinase inhibitors. FoxO1’s effects on the survival of photoreceptors were studied by infecting 661W cells with ether wild type or mutant FoxO1 adenovirus. GeneChip analysis of FoxO target genes was performed by using LCM (laser capture microdissection)–obtained photoreceptors from Irs2 –/– mice.The changes of several FoxO1 target genes were verified by real–time RT–PCR.
RT–PCR showed that FoxO isoforms FoxO1 and FoxO3a are expressed in the photoreceptors in vivo. Treatment of 661W cells with either insulin or IGF1 led to time and dose–dependent phosphorylation and degradation of FoxO1. This can be prevented by preincubation with the PI3K inhibitor LY294002 or wortmannin but not MAP kinase inhibitor PD98059. Overexpression of constitutively active FoxO1 in 661W cells led to a significant cell death via apoptosis. In contrast, infection of wild type FoxO1 had no effect on the cell survival. Using the Affymetrix array, we found dramatic gene transcription changes of 3641genes in LCM–captured photoreceptors from Irs2–/– mice compared to the wild type. Among these 3641 genes, we found 507 genes, which may be potentially regulated by FoxO1. In addition to several known FoxO–target genes including Bim, MnSOD, Catalase, and Gadd45, we identified several potential novel FoxO target genes like Faim and Pde6b that may be important in the photoreceptors. Furthermore, the protein level of Bim was found to be up–regulated by constitutively active FoxO1 in 661W cells and this Bim up–regulation may be critical for FoxO1–induced photoreceptors cell death.
These data suggest that FoxO1 is not only expressed in photoreceptors in vivo but also regulated by physiologically important stimuli for the survival of photoreceptors. It supports a potential role for insulin/ IGF1 to regulate FoxO through the Irs2→ PI3K→ Akt signaling cascade in the development and survival of photoreceptors and its dysregulation might contribute to neurodegenrative diseases of the retina.
This PDF is available to Subscribers Only