MOLECULAR MECHANISMS AND PUTATIVE SIGNALING EVENTS CONTROLLING UTROPHIN EXPRESSION IN MAMMALIAN SKELETAL-MUSCLE FIBERS

The absence of full-length dystrophin molecules in skeletal muscle fib res results in the most severe form of muscular dystrophy, the Duchenn e form (DMD). Several years ago, an autosomal homologue to dystrophin, termed utrophin, was identified. Although utrophin is expressed along the sarcolemma in developing, regenerating and DMD muscles, it noneth eless accumulates at the postsynaptic membrane of the neuromuscular ju nction in both normal and DMD adult muscle fibres. Due to the high deg ree of sequence identity between dystrophin and utrophin, it has been previously suggested that utrophin could in fact functionally compensa te for the lack of dystrophin. Recent studies using transgenic mouse m odel systems have directly tested this hypothesis and revealed that up regulation of utrophin throughout dystrophic muscle fibres represents indeed, a viable approach for the treatment of DMD. Current studies ar e therefore focusing on the elucidation of the various regulatory mech anisms presiding over expression of utrophin in muscle fibres in attem pts to ultimately identify small molecules which could systematically increase utrophin levels in extrasynaptic compartments of dystrophic m uscle fibres. This review presents some of the recent data relevant fo r our understanding of the transcriptional regulatory mechanisms invol ved in maintaining expression of utrophin at the neuromuscular junctio n. In addition, the contribution of specific cues originating from mot oneurons and the putative involvement of signalling events are also di scussed. (C) 1998 Elsevier Science B.V. All rights reserved.