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J. Biol. Chem., Vol. 283, Issue 28, 19781-19792, July 11, 2008

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Loss of Neuroprotective Survival Signal in Mice Lacking Insulin Receptor Gene in Rod Photoreceptor Cells^*

Ammaji Rajala, Masaki Tanito^¶, Yun Z. Le^||**, C. Ronald Kahn, and Raju V. S. Rajala^||1

From the Departments of Ophthalmology and ^||Cell Biology, and Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, the ^¶Department of Ophthalmology, Shimane University Faculty of Medicine, Izumo, Japan 693-8501, the ^**Department of Medicine and Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, and the Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215

Insulin receptor (IR) signaling provides a trophic signal for transformed retinal neurons in culture, but the role of IR activity in vivo is unknown. We previously reported that light causes increased tyrosine phosphorylation of the IR in vivo, which leads to the downstream activation of the phosphoinositide 3-kinase and Akt pathway in rod photoreceptor cells. The functional role of IR in rod photoreceptor cells is not known. We observed that light stress induced tyrosine phosphorylation of the IR in rod photoreceptor cells, and we hypothesized that IR activation is neuroprotective. To determine whether IR has a neuroprotective role on rod photoreceptor cells, we used the Cre/lox system to specifically inactivate the IR gene in rod photoreceptors. Rod-specific IR knock-out mice have reduced the phosphoinositide 3-kinase and Akt survival signal in rod photoreceptors. The resultant mice exhibited no detectable phenotype when they were raised in dim cyclic light. However, reduced IR expression in rod photoreceptors significantly decreased retinal function and caused the loss of photoreceptors in mice exposed to bright light stress. These results indicate that reduced expression of IR in rod photoreceptor cells increases their susceptibility to light-induced photoreceptor degeneration. These data suggest that the IR pathway is important for photoreceptor survival and that activation of the IR may be an essential element of photoreceptor neuroprotection.

Received for publication, March 26, 2008 , and in revised form, April 23, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants EY016507, EY00871, and NCRR (P20-RR17703) from the NEI. This work was also supported by Research to Prevent Blindness, Inc. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-4.

¹ To whom correspondence should be addressed: University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd., Oklahoma City, OK 73104. Tel.: 405-271-8255; Fax: 405-271-8128; E-mail: raju-rajala{at}ouhsc.edu.

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