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Stacey L Hose, Cheng Zhang, J Samuel Zigler, Jiang Qian, Debasish Sinha; Glial cells of the optic nerve and Persistent Fetal Vasculature (PFV) disease. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4215.
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© ARVO (1962-2015); The Authors (2016-present)
PFV is a human disease that results from failure of the fetal vasculature to regress normally. Failure of all or part of these vessels to regress can lead to serious congenital pathologies. The defects include congenitally small eye, cataract, glaucoma, intravitreal fibrovascular tissue and/or hemorrhage, and retinal detachment. PFV has been reported in other mammalian species, particularly in dogs, and in genetic mouse models. Studies with these animals have helped immensely with our current understanding of the disease. The focus of this study is to determine the role of glial cells of the optic nerve in PFV disease by studying a rat with mutations in both βA3/A1-crystallin (Cryba1) and branched-chain ketoacid dehydrogenase kinase (Bckdk).
Eyes fixed in 2% paraformaldehyde were used for immunohistochemistry for astrocytes (GFAP), oligodendrocytes (APC), blood vessels (lectin), axons (SMI 312) and myelin (myelin basic protein). Animals were perfused with 4% paraformaldehyde and post-fixed in 3% glutaraldehyde prior to electron microscopic analysis of the optic nerve. Human Proteome Microarray v2.0 (CDI, Nextgen Proteomics) was used to study protein-protein interactions.
Rats homozygous for mutations in both Cryba1 and Bckdk have severely affected glial populations (astrocytes and oligodendrocytes) of the optic nerve. The PFV phenotype is very severe and the entire fetal vasculature fails to regress. The retina in these double mutant rats is much thinner than normal, showing severe degeneration of the inner retinal layers. Protein-protein interaction studies indicate that βA3/A1-crystallin may regulate abnormal astrocyte migration during hyaloid vessel regression by modulating cortactin and src kinase-associated phosphoprotein 2 (SKAP2).
We have developed a novel animal model that mimics clinical signs of severe human PFV, a potentially blinding childhood disease, for which there are limited treatment options at the present time. Our data suggest that the degree of completeness and severity of the disease depends on both the glial and lens phenotype. The exact prevalence of PFV is unknown; however, a study on childhood blindness and visual loss in the United States showed that PFV accounts for about 5% of all cases of blindness. The clinical benefit in treating PFV is saving the eye from the secondary complications of the disease.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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