An examination of the rearrangement in synaptic connections (""""""""synapse elimination"""""""") occurring in neonatal rat and mouse muscles is proposed. The long-term goal is to understand what qualitative and quantitative roles this rearrangement plays in establishing the adult pattern of innervation of muscles. The project has five specific aims. (1) To examine the role of synapse elimination in the creation of motor units composed of muscle fibers which share the same differentiation or """"""""type"""""""". Recently, immunohistochemistry has been used to show that such fiber types appear during fetal development. We will explore how these early fiber types are arranged into motor units, using glycogen depletion to mark the fibers innervated by a single motor neuron and immunohistochemistry to determine the types of the marked fibers. We expect to be able to show whether synapse elimination has a qualitative role in determining the type composition of motor units. (2) To examine the role of innervation in fiber type differentiation in mammalian fetal muscle. We will use mouse mutants and administration of neurotoxins to produce aneurogenic or paralyzed fetal muscles and analyze the fiber types in these muscles by immunohistochemistry. (3) To examine neonatal muscles for evidence of selectivity in reinnervation. We will determine whether motor neurons show any selectivity in synapse formation for muscle fibers of a particular type or muscle fibers located in a particular muscle position. These experiments should give clues as to how it is that the order present in the innervation of muscle regions and fiber types arises during development. (4) To examine for readjustments in the innervation of muscle fibers occurring after the period of synapse elimination. Experiments have shown that at the end of synapse elimination motor units differ in size and type homogeneity from those in the adult, implying yet further readjustments in muscle innervation. We will examine motor units during the period following synapse elimination to provide further evidence for the occurrence of this rearrangement and its timing. (5) To examine the role of differential neural activity and synapse elimination. We will use stimulation of a portion of the innervation of a muscle to examine whether active axons have any competitive advantage over less active axons in the process of synapse elimination. All of the proposed experiments should further understanding of the development of synaptic connections in muscle.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020480-06
Application #
3400820
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1984-06-01
Project End
1991-05-31
Budget Start
1989-06-01
Budget End
1991-05-31
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Type
Schools of Arts and Sciences
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78713
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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