Aberrant development of neuromuscular junctions in glycosylation-defective Largemyd mice

Mice deficient in the glycosyltransferase Large are characterized by severe muscle and central nervous system abnormalities. In this study, we show that the formation and maintenance of neuromuscular junctions in Largemyd mice are greatly compromised. Neuromuscular junctions are not confined to the muscle endplate zone but are widely spread and are frequently accompanied by exuberant nerve sprouting. Nerve terminals are highly fragmented and binding of α-bungarotoxin to postsynaptic acetylcholine receptors (AChRs) is greatly reduced. In vitro, Largemyd myotubes are responsive to agrin but produce aberrant AChR clusters, which are larger in area and less densely packed with AChRs. In addition, AChR expression on the cell surface is diminished suggesting that AChR assembly or transport is defective. These results together with the finding that O-linked glycosylation at neuromuscular junctions of Largemyd mice is compromised indicate that the action of Large is necessary for proper neuromuscular junction development.