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The Journal of Neuroscience, February 2, 2005, 25(5):1240-1248; doi:10.1523/JNEUROSCI.3664-04.2005

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Cellular/Molecular
Insulin Receptor Substrate 2 Is Essential for Maturation and Survival of Photoreceptor Cells

Xianjin Yi,^1 * Markus Schubert,^1 * Neal S. Peachey,^2,3 Kiyoshi Suzuma,⁴ Deborah J. Burks,¹ Jake A. Kushner,¹ Izumi Suzuma,⁴ Christopher Cahill,⁴ Carrie L. Flint,¹ Matthew A. Dow,¹ Rebecca L. Leshan,¹ George L. King,⁴ and Morris F. White¹

¹Howard Hughes Medical Institute, Children's Hospital Boston, Boston, Massachusetts 02115, ²Research Service, Cleveland Veterans Affairs Medical Center, Cleveland, Ohio 44106, ³Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, and ⁴Section for Vascular Cell Biology, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215

Insulin receptor substrates (Irs-proteins) integrate signals from the insulin and insulin-like growth factor-1 (IGF1) receptors with other processes to control cellular growth, function, and survival. Here, we show that Irs2 promoted the maturation and survival of photoreceptors in the murine retina immediately after birth. Irs2 was mainly localized to the outer plexiform layer as well as to photoreceptor inner segments. It was also seen in ganglion cells and inner plexiform layer but in smaller amounts. Compared with control littermates, Irs2 knock-out mice lose 10% of their photoreceptors 1 week after birth and up to 50% by 2 weeks of age as a result of increased apoptosis. The surviving photoreceptor cells developed short organized segments, which displayed proportionally diminished but otherwise normal electrical function. However, IGF1-stimulated Akt phosphorylation was barely detected, and cleaved/activated caspase-3 was significantly elevated in isolated retinas of Irs2^-/- mice. When diabetes was prevented, which allowed the Irs2^-/- mice to survive for 2 years, most photoreceptor cells were lost by 16 months of age. Because apoptosis is the final common pathway in photoreceptor degeneration, pharmacological strategies that increase Irs2 expression or function in photoreceptor cells could be a general treatment for blinding diseases such as retinitis pigmentosa.

Key words: Irs2; IGF1 signaling; retina; photoreceptor degeneration; apoptosis; knock-out mice

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Received Sep 5, 2004; revised December 7, 2004; accepted December 9, 2004.

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