Experiments are proposed to investigate the role of the glial cells at the neuromuscular junction (the """"""""terminal Schwann cells"""""""") in muscle reinnervation and sprouting. The long term objective is to understand mechanisms of synapse formation and maintenance. Much of the previous work on the formation and maintenance of the neuromuscular junction has assumed that the nerve and muscle fiber interact directly. However, recent experiments have implicated the Schwann cells as important players as well. Results obtained during the last grant period suggest that Schwann cells, through the process they extend, induce and guide nerve growth. Here it is proposed to determine whether Schwann cell guidance is a mechanism of muscle reinnervation and sprouting. The role of Schwann cells in regression of extra nerve processes formed during reinnervation will also be explored. Images of vitally stained components of the neuromuscular junction (the Schwann cells, the nerve terminals, and the acetylcholine receptors) will be caused by repeated viewing of the same junctions in living animals. It will thus be possible to determine whether Schwann cells for muscle processes lead or follow axon growth and regression. To test the importance of Schwann cells for muscle reinnervation and sprouting, two additional types of experiments are planned. First, Schwann cells at vitally stained junctions will be ablated by a laser microbeam or by use of dye-activated cell killing. The ability of axons to extend and to reinnervate junctions will then be determined in the absence of Schwann cells. A second approach will make use of an observation of the previous grant period: denervation of muscle in neonatal rats results in loss of terminal Schwann cells, apparently by apoptotic death. This Schwann cell loss suggest these cells are trophically dependent upon axonal contact; the mechanism of this trophic dependence will be investigated by attempts to effect the rescue of denervated Schwann cells via administration of certain trophic factors. This Schwann cell loss also affords an opportunity to investigate the consequences of absence of Schwann cells for muscle reinnervated and for axonal sprouting. Both of these phenomena have been reported to be deficient in the neonate in comparison with adult muscle. We will therefore investigate how muscle fibers are reinnervated and how motor neurons sprout in the absence of terminal Schwann cells. Collectively, these experiments will provide additional knowledge about the role of Schwann cells in muscle reinnervation and sprouting. The experiments should reveal basic mechanisms of nerve growth. They should also further our knowledge about these interesting, but largely neglected components of the neuromuscular synapse.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology B Subcommittee 2 (NEUB)
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Nichols, Paul L
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University of Texas Austin
Schools of Arts and Sciences
United States
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Lee, Young Il; Thompson, Wesley J; Harlow, Mark L (2017) Schwann cells participate in synapse elimination at the developing neuromuscular junction. Curr Opin Neurobiol 47:176-181
Lee, Young Il; Li, Yue; Mikesh, Michelle et al. (2016) Neuregulin1 displayed on motor axons regulates terminal Schwann cell-mediated synapse elimination at developing neuromuscular junctions. Proc Natl Acad Sci U S A 113:E479-87
Kang, Hyuno; Tian, Le; Mikesh, Michelle et al. (2014) Terminal Schwann cells participate in neuromuscular synapse remodeling during reinnervation following nerve injury. J Neurosci 34:6323-33
Smith, Ian W; Mikesh, Michelle; Lee, Young il et al. (2013) Terminal Schwann cells participate in the competition underlying neuromuscular synapse elimination. J Neurosci 33:17724-36
Li, Yue; Lee, Young il; Thompson, Wesley J (2011) Changes in aging mouse neuromuscular junctions are explained by degeneration and regeneration of muscle fiber segments at the synapse. J Neurosci 31:14910-9
Brill, Monika S; Lichtman, Jeff W; Thompson, Wesley et al. (2011) Spatial constraints dictate glial territories at murine neuromuscular junctions. J Cell Biol 195:293-305
Li, Yue; Thompson, Wesley J (2011) Nerve terminal growth remodels neuromuscular synapses in mice following regeneration of the postsynaptic muscle fiber. J Neurosci 31:13191-203
Lee, Young Il; Mikesh, Michelle; Smith, Ian et al. (2011) Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons. Dev Biol 356:432-44
Kang, Hyuno; Tian, Le; Son, Young-Jin et al. (2007) Regulation of the intermediate filament protein nestin at rodent neuromuscular junctions by innervation and activity. J Neurosci 27:5948-57
Hayworth, Christopher R; Moody, Susan E; Chodosh, Lewis A et al. (2006) Induction of neuregulin signaling in mouse schwann cells in vivo mimics responses to denervation. J Neurosci 26:6873-84

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