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Raju V S Rajala, Yuhong Wang, Ammaji Rajala; Insulin-like growth factor 1 receptor is necessary for rod photoreceptor structure and function. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2353.
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© ARVO (1962-2015); The Authors (2016-present)
We previously reported the neuroprotective role of insulin receptor in photoreceptor neurons. The insulin growth factor 1 receptor (IGF-1R) is highly related in sequence and structure to the insulin receptor and shares 70% sequence identity overall and 84% identity within the tyrosine kinase domain. The role of IGF-1R in photoreceptor function is not known. To investigate the significance of IGF-1R in rod photoreceptors, we disrupted the IGF-1R gene specifically in mouse rod photoreceptors, characterized the effect on retinal function and structure, and studied the role of IGF-1R signaling in rod photoreceptor cells.
The activation of the IGF-1R/PI3K/Akt pathway was analyzed using specific antibodies. In vivo IGF-1R signaling was studied in animals exposed to either physiological light or constant light stress. Rod-specific IGF-1R knockout mice were generated by mating mouse opsin promoter-controlled Cre mice (i75Cre) with floxed IGF-1R mice. Loss of IGF-1R in rod photoreceptor was confirmed by immunoblot analysis. Photoreceptor structural integrity was measured by optical coherence tomography (OCT) and quantitative morphometry (outer nuclear layer [ONL] thickness). Rod and cone photoreceptor function was assessed by electroretinography (ERG). Cell death was monitored using in situ TUNEL staining to localize apoptosis. We counted the number of TUNEL-positive cells.
Our studies indicate that light stress results in an increase in tyrosine phosphorylation of IGF-1R and an increase in PI3K enzyme activity in anti-phosphotyrosine and anti-IGF-1R immunoprecipitates of rod outer segments and retinal homogenates. We found a significant activation of Akt in light-stressed retinas, indicating activation of the Akt survival pathway downstream of IGF-1R activation. Disruption of IGF-1R specifically in rods decreased IGF-1R expression and significantly decreased rod function without affecting cone function at 18 weeks. ONL thickness and OCT analysis in IGF-1R KO mouse retinas indicated a significant loss of photoreceptor outer nuclei and increased TUNEL-positive staining compared with wild-type mice, suggesting rod photoreceptor degeneration.
These findings clearly suggest that the IGF-1R pathway is important for photoreceptor function and survival. Activation of IGF-1R may be an essential element of photoreceptor neuroprotection.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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