Dystroglycan in central nervous system development and disease

Walker-Warburg syndrome (WWS), Muscle-Eye-Brain disease (MEB), and Fukuyama-type congenital muscular dystrophy (FCMD) are linked to genes that encode known and putative glycosyltransferases in the biosynthetic pathway of dystroglycan. The purpose of these studies was to define the function of dystroglycan in the CNS and its relevance to brain and eye in defects in congenital muscular dystrophies (CMD).; Biochemical analysis of WWS brain showed the presence of dystroglycan in a hypoglycosylated state with reduced ligand-binding affinity. Furthermore, embryonic loss of dystroglycan in the mouse produced brain and eye defects broadly similar to the clinical spectrum of WWS, demonstrating that dystroglycan is the key glycosyltransferase substrate in the pathogenic mechanism of WWS.; Cerebral cortex development was studied in mouse strains with tissue-specific loss of dystroglycan to elucidate the pathogenic mechanism of type II lissencephaly, a hallmark of WWS, MEB, and FCMD. Neuron-specific loss of dystroglycan in the mouse cerebral cortex did not disrupt the laminar development of the cortex; however, tissue specific loss of dystroglycan in the whole brain produced breaches of the glia limitans and glial and neuronal heterotopia which resemble the cobblestone complex. In the cerebral cortex, glial expression of dystroglycan is critical for the stability of the glia limitans and the scaffolding for neuron migration.; Cerebellar development was studied in mouse strains with distinct spatial and temporal loss of dystroglycan to elucidate the pathogenic mechanism of cerebellar dysplasia, a common feature of WWS, MEB, and FCMD. In mice with brain-specific loss of dystroglycan expression, breaches of the glia limitans were associated with fused cerebellar lobules and granule neuron ectopia. Expression of DG in granule cells was not necessary for their migration; however, Purkinje cell specific loss of dystroglycan produced granule neuron heterotopia, demonstrating a novel role for dystroglycan in neuron migration.; These studies identify dystroglycan as the key glycosyltransferase target in the pathogenesis of severe forms of CMD and reveal multiple roles for dystroglycan in the development and physiology of the CNS.