Experiments will be conducted to investigate the role of synaptic glia (terminal Schwann cells) in the formation and maintenance of neuromuscular junctions (nmjs). Recent evidence suggests that these glia explain many of the responses to loss of muscle innervation: these cells apparently extend processes that induce and guide growth of nerve sprouts. Here it is proposed to rigorously test the importance of these cells by vitally imaging the cellular components of the nmj during recovery from nerve injuries. Muscle acetylcholine receptors will be labeled with rhodamine-alpha-bungarotoxin. Doubly transgenic mice expressing fluorescent proteins (CFP and GFP) of different colors in their axons and Schwann cells will allow visualization of these components as well. By repeated imaging of the same nmjs in living animals it will be possible to determine whether Schwann cell processes lead or follow several forms of axon growth and regression, whether Schwann cell processes grow in a direct manner to synaptic sites in muscle, and whether the growth induced in response to nerve injuries actually disrupts existing synaptic connections. In addition to these vital observations, Schwann cells will be manipulated in the living animal. First, these cells will be ablated and the consequences for synaptic maintenance and repair evaluated. Second, additional transgenic animals will be prepared in which it will be possible to induce selectively the expression of specific genes in Schwann cells and examine the consequences for muscle innervation. Initially these experiments will employ a dominant negative receptor for a trophic factor implicated in the previous application period as important for the maintenance of Schwann cells. Taken together these experiments should add to the recent explosion of information about synaptic glia. They also will help us understand the growth of nerves in muscles by sprouting, the major means by which muscle strength is maintained following loss of motor neurons in neurodegenerative disease or peripheral nerve lesions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37NS020480-16
Application #
6287487
Study Section
Special Emphasis Panel (ZRG1-SSS-Q (01))
Program Officer
Nichols, Paul L
Project Start
1984-06-01
Project End
2004-12-31
Budget Start
2001-03-01
Budget End
2001-12-31
Support Year
16
Fiscal Year
2001
Total Cost
$331,000
Indirect Cost
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78712
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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