Defective peripheral nerve myelination and neuromuscular junction formation in fukutin-deficient chimeric mice.

Dystroglycan is a central component of the dystrophin-glycoprotein complex that links the extracellular matrix with cytoskeleton. Recently, mutations of the genes encoding putative glycosyltransferases were identified in several forms of congenital muscular dystrophies accompanied by brain anomalies and eye abnormalities, and aberrant glycosylation of alpha-dystroglycan has been implicated in their pathogeneses. These diseases are now collectively called alpha-dystroglycanopathy. In this study, we demonstrate that peripheral nerve myelination is defective in the fukutin-deficient chimeric mice, a mouse model of Fukuyama-type congenital muscular dystrophy, which is the most common alpha-dystroglycanopathy in Japan. In the peripheral nerve of these mice, the density of myelinated nerve fibers was significantly decreased and clusters of abnormally large non-myelinated axons were ensheathed by a single Schwann cell, indicating a defect of the radial sorting mechanism. The sugar chain moiety and laminin-binding activity of alpha-dystroglycan were severely reduced, while the expression of beta1-integrin was not altered in the peripheral nerve of the chimeric mice. We also show that the clustering of acetylcholine receptor is defective and neuromuscular junctions are fragmented in appearance in these mice. Expression of agrin and laminin as well as the binding activity of alpha-dystroglycan to these ligands was severely reduced at the neuromuscular junction. These results demonstrate that fukutin plays crucial roles in the myelination of peripheral nerve and formation of neuromuscular junction. They also suggest that defective glycosylation of alpha-dystroglycan may play a role in the impairment of these processes in the deficiency of fukutin.