Dach2-Hdac9 signaling regulates reinnervation of muscle endplates

Muscle denervation resulting from injury, disease or aging results in impaired motor function. Restoring neuromuscular communication requires axonal regrowth and endplate reinnervation. Muscle activity inhibits the reinnervation of denervated muscle. The mechanism by which muscle activity regulates muscle reinnervation is poorly understood. Dach2 and Hdac9 are activity-regulated transcriptional co-repressors that are highly expressed in innervated muscle and suppressed following muscle denervation. Dach2 and Hdac9 control the expression of endplate-associated genes such as those encoding nicotinic acetylcholine receptors (nAChRs). Here we tested the idea that Dach2 and Hdac9 mediate the effects of muscle activity on muscle reinnervation. Dach2 and Hdac9 were found to act in a collaborative fashion to inhibit reinnervation of denervated mouse skeletal muscle and appear to act, at least in part, by inhibiting denervation-dependent induction of Myog and Gdf5 gene expression. Although Dach2 and Hdac9 inhibit Myog and Gdf5 mRNA expression, Myog does not regulate Gdf5 transcription. Thus, Myog and Gdf5 appear to stimulate muscle reinnervation through parallel pathways. These studies suggest that manipulating the Dach2-Hdac9 signaling system, and Gdf5 in particular, might be a good approach for enhancing motor function in instances where neuromuscular communication has been disrupted.