Ectopia of meningeal fibroblasts and reactive gliosis in the cerebral cortex of the mouse model of muscle-eye-brain disease.

Congenital muscular dystrophies with brain malformations, such as muscle-eye-brain disease, exhibit neural ectopias caused by overmigration of neurons. Such overmigration is evident in protein O-mannose beta-1,2-N-acetylglucosaminyltransferase (POMGnT1) knockout mouse, a model of muscle-eye-brain disease, caused by breaches in the pial basement membrane. We hypothesize that breaches in pial basement membrane disrupt the neural-meningeal boundary, resulting in ectopia of meningeal fibroblasts in the cerebral cortex and reactive gliosis. To test this hypothesis, the cerebral cortices of developing and adult POMGnT1 knockout mice were analyzed by immunostaining with cell-specific markers and by electron microscopy. The upper half of the cerebral cortex in the knockout mouse contained increased numbers of fibroblasts closely associated with capillaries. During development of the cerebral cortex in the knockout mice, breaches in pial basement membrane allowed emigration of overmigrated neurons into the developing pia-arachnoid, scattering its mesenchymal cells throughout the diffuse cell zone and resulting in ectopia of mesenchyme-derived fibroblasts in the upper half of the cortex. Glial fibrillary acidic protein (GFAP) immunostaining revealed that the upper half of the cerebral cortex in the knockout also contained increased numbers of cells with morphologies typical of reactive astrocytes compared with the wild type. Moreover, most of the GFAP-positive reactive astrocytes were in close contact with ectopic fibroblasts, suggesting that they were induced by the fibroblasts. Collectively, the data support the hypothesis that the cerebral cortex of POMGnT1 knockout mice is characterized by migration defects leading to disruption of the pia-arachnoid, ectopia of fibroblasts in the cortex, and reactive gliosis.