ROLE OF NEUREGULIN IN NEUROMUSCULAR SYNAPSE FORMATION

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The formation of neuromuscular synapses requires a series of inductive interactions between presynaptic motor nerve terminals and postsynaptic muscle fibers, resulting in the formation of highly specialized pre- and post-synaptic membranes. One aspect of postsynaptic differentiation is the up-regulation of muscle acetylcholine receptor (AChR) expression selectively in synaptic nuclei of myofibers. Neuregulin (NRG), a potential signal for regulating such synapse-specific transcription, and its receptors are localized to neuromuscular synapses. NRG is synthesized both by motor neurons and muscle cells and activates AChR gene expression in cultured muscle cells. Because NRG is synthesized both by motor neurons and muscle cells and activates AChR gene expression in cultured muscle cells. Because NRG is also expressed in endocardial tissues and is required for heart development, mutant mice lacking NRG expression die at embryonic day 10, prior to neuromuscular synapse formation, due to heart malformation. Therefore, the role that NRG may play in synapse formation during development in vivo cannot be evaluated in NRG null- mutant mice. This proposal is devoted to study the role NRG may have in neuromuscular synapse formation. The general approach in this study is to produce mice lacking NRG expression selective in skeletal muscle or in motor neurons, by crossing study is to produce mice lacking NRG expression selectively in skeletal muscle or in motor neurons, by crossing NRG/flox/flox mice with NRG+/-; MLCcre or NRG+/-; HB9cre mice. The formation of neuromuscular synapses will be analyzed by immunohistochemical procedures that will allow me to assess both presynaptic and postsynaptic differentiation. This study will provide information on the function of NRG signaling in neuromuscular synapse formation and may provide insight into signaling mechanisms at interneuronal synapses in the brain.