Reactive gliosis of astrocytes and Müller glial cells in retina of POMGnT1-deficient mice

Protein O-linked mannose beta1, 2-N-acetylglucosaminyltransferase 1 (POMGnT1) is an enzyme that catalyzes the transfer of N-acetylglucosamine to O-mannose of glycoproteins. Alpha-dystroglycan, a substrate of POMGnT1, is concentrated around the blood vessels, in the outer plexiform layer (OPL), and in the inner limiting membrane (ILM) of the retina. Mutations of the POMGnT1 gene in humans cause muscle-eye-brain (MEB) disease. Several ocular abnormalities including retinal dysplasia, ERG abnormalities, and retinal detachments have been reported in patients with MEB. We have analyzed the eyes of POMGnT1-deficient mice, generated by standard gene targeting technique, to study the retinal abnormalities. Clinical examination of adult mutant mice revealed a high incidence (81% by 12-months-of-age) of retinal detachments. Sheathing of the retinal vessels and the presence of ectopic fibrous tissues around the optic nerve head were also found. Histological examinations showed focal retinal detachment associated with GFAP immunopositivity. The ILM of the mutant mice was disrupted with ectopic cells near the disruptions. The expression of Dp71, a shorter isoform of dystrophin, was severely reduced in the ILM and around retinal blood vessels of POMGnT1-deficient mice. The expression of Dp427, Dp260, Dp140 were also reduced in the OPL of the mutant mice. Electroretinographic (ERG) analyses showed reduced a- and b-wave amplitudes. Examinations of flat mounts revealed abnormal vascular network associated with highly irregular astrocytic processes. In addition, ER-TR7-positive fibrous tissue was found closely associated with reactive astrocytes especially around the optic nerve head. Our results suggest that altered glycosylation of alpha-DG may be responsible for the reactive gliosis and reticular fibrosis in the retina, and the subsequent developments of retinal dysplasia, abnormal ERGs, and retinal detachment in the mutant mice.