Effects of fukutin deficiency in the developing mouse brain

The major pathological change in Fukuyama-type congenital muscular dystrophy brain is polymicrogyria. Pathological studies of Fukuyama-type congenital muscular dystrophy brain indicated that protrusion of neurons into the subarachnoid space through breaches in the glia limitans-basal lamina complex is a cardinal pathogenic process in this condition. It remains undetermined, however, whether the defect causing this abnormal migration resides in the migrating neurons or in the glia limitans-basal lamina complex. To elucidate the pathogenesis of brain abnormalities in Fukuyama-type congenital muscular dystrophy, we analyzed histologically and immunohistochemically the developing forebrain in fukutin-deficient chimeric mice and compared it with that in controls (n=4 in each group). In chimeric embryos, ectopia became apparent as early as embryonic day 14, and laminar organization became progressively distorted. The basal lamina of the cortical surface in chimeras showed defects at E14, coinciding with the earliest time point at which ectopia were detected. Immunohistochemical analysis of glycosylated α-dystroglycan showed progressive defects coincidental with the disruption of the basal lamina. Neuronal migration was not affected in chimeras, as determined by detection of bromodeoxyuridine-labeled neurons. Extension of radial glial fibers was intact in chimeras. Taken together, disruption of the basal lamina, caused by the loss of interaction between hypoglycosylated α-dystroglycan and its ligands, plays a key role in the pathogenesis of cortical dysplasia in Fukuyama-type congenital muscular dystrophy.