POSTSYNAPTIC ABNORMALITIES AT THE NEUROMUSCULAR-JUNCTIONS OF UTROPHIN-DEFICIENT MICE

Utrophin is a dystrophin-related cytoskeletal protein expressed in man y tissues. It is thought to link F-actin in the internal cytoskeleton to a transmembrane protein complex similar to the dystrophin protein c omplex (DPC). At the adult neuromuscular junction (NMJ), utrophin is p recisely colocalized with acetylcholine receptors (AChRs) and recent s tudies have suggested a role for utrophin in AChR cluster formation or maintenance during NMJ differentiation. We have disrupted utrophin ex pression by gene targeting in the mouse, Such mice have no utrophin de tectable by Western blotting or immunocytochemistry. Utrophin-deficien t mice are healthy and show no signs of weakness, However, their NMJs have reduced numbers of AChRs (alpha-bungarotoxin [alpha-BgTx] binding reduced to similar to 60% normal) and decreased postsynaptic folding, though only minimal electrophysiological changes. Utrophin is thus no t essential for AChR clustering at the NMJ but may act as a component of the postsynaptic cytoskeleton, contributing to the development or m aintenance of the postsynaptic folds. Defects of utrophin could underl ie some forms of congenital myasthenic syndrome in which a reduction o f postsynaptic folds is observed.