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

Abstract

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.

Prompt meningeal reconstruction mediated by oxygen-sensitive AKAP12 scaffolding protein after central nervous system injury

“…1a, left panel). The AKAP12 signal completely overlapped those of fibronectin 27 and ERTR7 (ref. 28), markers of meningeal cells (Fig.…”

Conditional knockout of protein O‐mannosyltransferase 2 reveals tissue‐specific roles of O‐mannosyl glycosylation in brain development

“…POMGnT1 knockout exhibits ectopic fibroblasts in the upper half of the neocortex (Yang et al, 2007). Therefore, immunostaining with ER-TR7 (a fibroblast marker) was carried out.…”

Possible Diverse Roles of Fukutin: More Than Basement Membrane Formation?

“…Morphological abnormalities of the basement membrane and the glia limitans have been reported in the CNS of FCMD (Fig. 2) (Nakano et al 1996;Takada et al 1987;Yamamoto et al 1997;Yamamoto et al 2010) and WWS (Beltrán-Valero de Bernabé 2002;Miller et al 1991) patients and in mouse models of FCMD (Chiyonobu et al 2005) and MEB (Yang et al 2007). Fragile basement membrane caused by hypoglycosylation GL: glia limitans, CP: cortical plate, WM: white matter, GM: germinal matrix, EP: ependymal cells, BM: basement membrane, As: endfeet of astrocytes Fig.…”

“…The clinical onset of LGMDs is late compared with that of congenital ones. Examples of animal models of -dystroglycanopathy are fukutin chimeric mice (Chiyonobu et al 2005;Masaki & Matsumura 2010), large myd mice (Lee et al 2005;Masaki & Matsumura 2010), large vls mice (Lee et al 2005;Masaki & Matsumura 2010), POMGnT1 knockout mice (Yang et al 2007) and P0-DG null mice (Masaki & Matsumura 2010). www.intechopen.com -dystroglycanopathy shows the reduced glycosylation of -DG at the cell/basement membrane.…”