Figure 6

Model of MyoD regulation in adult muscle fibres. MD6.0-lacZ element(s) constituting a 'Fibre Enhancer' integrate two signals, positive auto-regulation by MyoD and nerve/activity-dependence, and target them onto the native MyoD promoter. Activity effects on the DRR/PRR region comprise suppression of PRR (grey line) and activation of DRR, which predominates in the intact DRR/PRR region (black lines). Another activity-dependent 'Denervation Enhancer' mediates the activation of MyoD in adult fibres after denervation by one of two routes. Activity may suppress this enhancer, which otherwise directly activates the basal promoter (dashed lines). Alternatively, this enhancer may co-operate with the PRR (dotted arrow) to activate the basal promoter when direct effects of nerve on the DRR/PRR region (solid lines) are absent. In either case, upon denervation the poised low-level MyoD expression driven through MD6.0-lacZ Fibre Enhancer is lost, but MyoD rises driven by the Denervation Enhancer. Despite the increased level of nuclear MyoD protein, lack of nerve/activity prevents maximal activation of the MD6.0-lacZ transgene. In innervated fibres, we propose that subtle differences in activity in otherwise similar fibres lead to changes in MyoD expression that are amplified by positive feedback (grey arrow) through the Fibre Enhancer, thereby explaining fibre-to-fibre variation in MD6.0-lacZ and MyoD expression. Active MyoD in these fibres may mediate some effects of the nerve, such as the rate of anabolism (open arrow). Elsewhere in the gene, elements missing from MD6.0-lacZ control expression in, for example, early embryonic myogenic cells and other myoblasts.