A CNS-specific hypomorphic Pdgfr-beta mutant model of diabetic retinopathy

Jadeja, Shalini and Mort, Richard L. and Keighren, Margaret and Hart, Alan W. and Joynson, Russell and Wells, Sara and Potter, Paul K. and Jackson, Ian J. (2013) A CNS-specific hypomorphic Pdgfr-beta mutant model of diabetic retinopathy. Investigative Ophthalmology and Visual Science, 54 (5). pp. 3569-3578. ISSN 0146-0404

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Abstract

PURPOSE: A mouse mutant identified during a recessive N-ethyl-N-nitrosourea (ENU) mutagenesis screen exhibited ocular hemorrhaging resulting in a blood-filled orbit, and hence was named "redeye." We aimed to identify the causal mutation in redeye, and evaluate it as a model for diabetic retinopathy (DR). METHODS: The causative gene mutation in redeye was identified by haplotype mapping followed by exome sequencing. Glucose tolerance tests, detailed histologic and immunofluorescence analyses, and vascular permeability assays were performed to determine the affect of redeye on glucose metabolism, pericyte recruitment, and the development of the retinal vasculature and blood-retinal barrier (BRB). RESULTS: A mutation was identified in the Pdgfrb gene at position +2 of intron 6. We show that this change causes partial loss of normal splicing resulting in a frameshift and premature termination, and, therefore, a substantial reduction in normal Pdgfrb transcript. The animals exhibit defective pericyte recruitment restricted to the central nervous system (CNS) causing basement membrane and vascular patterning defects, impaired vascular permeability, and aberrant BRB development, resulting in vascular leakage and retinal ganglion cell apoptosis. Despite exhibiting classic features of diabetic retinopathy, redeye glucose tolerance is normal. CONCLUSIONS: The Pdgfrb(redeye/redeye) mice exhibit all of the features of nonproliferative DR, including retinal neurodegeneration. In addition, the perinatal onset of the CNS-specific vascular phenotype negates the need to age animals or manage diabetic complications in other organs. Therefore, they are a more useful model for diseases involving pericyte deficiencies, such as DR, than those currently being used.

Item Type:
Journal Article
Journal or Publication Title:
Investigative Ophthalmology and Visual Science
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2800/2804
Subjects:
ID Code:
84125
Deposited By:
Deposited On:
20 Jan 2017 14:24
Refereed?:
Yes
Published?:
Published
Last Modified:
24 Jun 2020 04:16