Retinal Insulin Receptor Deficiency Disrupts Retinal Development

Abstract

Abstract: : Purpose: Insulin receptors (IR) in the retina possess constitutive activity similar to those in brain, but the function of retinal IR signaling is not completely understood. The purpose of this study was to determine the effect of insulin receptor deficiency on the retina. Methods: The IR-/- mouse phenotype is lethal within 3 days after birth from diabetic ketoacidosis. IR-/- mice that were given back the IR gene under the transthyretin (TTR) promoter are rescued from death and a diabetic phenotype. The TTR promoter directs expression of the IR to the liver, pancreatic ß cells, and the choroid plexus of the brain. Genotyping was performed by PCR of genomic tail DNA. The retinas from TTR+ IR-/- mice were compared directly to TTR+ IR+/+ mice by immunohistochemistry, immunoblotting, and ex vivo insulin stimulation. Results: The TTR+ IR-/- mice reproduced normally and had no significant systemic morphological abnormalities compared to control TTR+ IR+/+ mice. The TTR transgene was also distributed in normal Mendelian ratios. Retina and skeletal muscle from TTR+ IR-/- mice do not express the IR, but the IGF-1R and IRS-1 was expressed normally in retina. Rhodopsin expression within the photoreceptor cell layer was significantly diminished in TTR+ IR-/- mice compared to TTR+ IR+/+ mice. Retinas from TTR+ IR-/- mice treated ex vivo with insulin had reduced Akt phosphorylation. Conclusions: The insulin receptor is required for normal retinal development. These findings may have implications for treatments of retinal degenerations.

Keywords: transgenics/knock-outs • retina • growth factors/growth factor receptors