Regulation of Skeletal Muscle Innervation and ALS Pathogenesis by MicroRNA 206




Williams, Andrew H.

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Motor neurons and the skeletal muscle fibers they innervate maintain an intimate relationship that requires bidirectional signaling for the establishment and maintenance of neuromuscular synapses and muscle function. Abnormalities in the regulation of neuromuscular gene expression often result in neuropathies and myopathies, reflecting the intimate communication between muscle and motor nerve. In this thesis, I present my studies on the function of microRNAs in neuromuscular synapse regeneration and neurodegenerative disease. First, I show that the expression of a muscle-specific microRNA (miRNA), miR-206, is dramatically upregulated following surgical denervation of skeletal muscle and in a mouse model of amyotrophic lateral sclerosis (ALS). The responsiveness of the miR-206 gene to the state of motor innervation is dependent on binding sites for MyoD in an upstream enhancer. Based on the upregulation of miR-206 following denervation and its synapse-enriched expression pattern, I hypothesized that miR-206 is an important regulator of neuromuscular junction (NMJ) physiology and I generated miR-206 mutant mice. Using these mice, I demonstrated that miR-206 is an essential regulator of neuromuscular synapse reinnervation following nerve injury. The requirement of miR-206 for efficient reinnervation reflects, at least in part, its repressive influence on histone deacetylase 4 (HDAC4). I also explored another function of miR-206, as an essential modulator of retrograde growth factor signaling during the progression of neurodegenerative disease. By crossing miR-206 mutant mice to G93A-SOD1 transgenic mice, which express a mutant form of superoxide dismutase (SOD), I determined that the loss of miR-206 accelerates the pathogenesis of ALS due to the loss of functional NMJs. Thus, the results of my thesis research demonstrate that miR-206 functions as a sensor of motor innervation and regulates a retrograde signaling pathway required for nerve-muscle interactions during stress and disease.

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