Subject(s)
Disease Models, Animal , Drug Discovery/methods , Mice , Neovascularization, Pathologic/drug therapy , Retinal Diseases/drug therapy , Animals , Drug Evaluation, Preclinical/methods , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/physiopathology , Retinal Diseases/genetics , Retinal Diseases/physiopathologyABSTRACT
Recent gene expression studies on mouse models for retinal degeneration identified deregulation of Pituitary tumor transforming gene 1 (Pttg1) as a potential susceptibility factor involved in photoreceptor cell death. Pttg1 is a transcription regulatory protein involved in sister chromatid segregation, and Pttg1(-/-) mice exhibit testicular and splenic hypoplasia, thymic hyperplasia, aberrant cell cycle progression, chromosome instability, and impaired glucose homeostasis leading to diabetes, particularly in older males. Due to Pttg1 deregulation in dystrophic retinas, we characterized Pttg1(-/-) retinas using Hematoxylin and Eosin (H&E) staining, immunohistochemistry (IHC), and electroretinography (ERG). Seven month old Pttg1(-/-) mice were also examined for a diabetic retinopathy phenotype using Fluorescein Angiography (FA) to test for neovascularization. Our data reveal that up to 9 months of age, Pttg1(-/-) retinas have a healthy morphology and normal photoreceptor function. This study lays the groundwork for further investigation into the relevance of Pttg1 in retinal dystrophy.
Subject(s)
Neoplasm Proteins/genetics , Retina/metabolism , Animals , Base Sequence , Choroidal Neovascularization/genetics , DNA Primers , Electroretinography , Female , Fluorescein Angiography , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , SecurinABSTRACT
PURPOSE: The effects of aging and light exposure on cone photoreceptor survival were compared between mouse retinas of neural retina leucine zipper knockout (Nrl(-/-)) mice and double-knockout mice lacking G-protein-coupled receptor kinase 1 (Nrl(-/-)Grk1(-/-)). METHODS: Mice were reared in total darkness, ambient cyclic light, or constant light, and their retinas were evaluated from 1 to 9 months of age using immunohistochemistry, electroretinography, and fluorescein angiography. Retinal gene expression and statistically significant probe sets were categorized using analysis software. Select gene expression changes were confirmed with quantitative RT-PCR. RESULTS: In contrast to retinas from Nrl(-/-), those from Nrl(-/-)Grk1(-/-) exhibit a progressive loss of the outer nuclear layer, retinal physiology deficits, and a higher rate of degeneration with increasing age that is independent of environmental light exposure. Changes in retinal neovascularization occur in the Nrl(-/-)Grk1(-/-) at 1 month, before the onset of significant cone functional deficits. Microarray analyses demonstrate statistically significant changes in transcript levels of more than 400 genes, of which the oncostatin M signaling pathway and the inflammatory disease response network were identified. CONCLUSIONS: These data demonstrate that the loss of functional Grk1 on the enhanced S-cone Nrl(-/-) background exacerbates age-related cone dystrophy in a light-independent manner, mediated partly through the inflammatory response pathway and neovascularization. According to these findings, Grk1 helps to maintain a healthy cone environment, and the Nrl(-/-)Grk1(-/-) mouse allows examination of the alternative roles of Grk1 in cone photoreceptor homeostasis.
