At vertebrate neuromuscular junctions, the transmission of signal from the nerve to the muscle which causes muscle contraction is mediated by the release of acetylcholine from the nerve terminal and the sensing of this molecule by the receptors in the muscle. This is accomplished by the clustering of acetylcholine receptors in the postsynaptic membrane opposite to the nerve terminal and the focal accumulation of synaptic vesicles which contain acetylcholine in the nerve terminal. The objective of this study is to understand the cellular and molecular mechanisms that govern the development of this prototypical synapse.
The specific aims are: 1) to understand the role of peptide growth factors that are bound to the extracellular matrix in the signaling of the postsynaptic development; 2) to study the signal transduction mechanisms in the formation of the acetylcholine receptor clusters; 3) to elucidate the function of postsynaptically associated cytoskeletal proteins in the formation of the acetylcholine receptor clusters; 4) to investigate the nature of the nerve-muscle interaction that leads to presynaptic differentiation. Tissue cultures of spinal cord neurons and muscle cells from amphibian embryos will be used as the model system in this study. A range of techniques, including microscopy, immuno- cytochemistry, protein biochemistry, molecular biology and electrophysiology, will be used to observe the development of the nerve terminal and the postsynaptic membrane in tissue culture. These studies should lead to advancement in our understanding of the biogenesis of this peripheral synapse. The principles garnered from this study should also be useful in understanding the synaptic development in the central nervous system. Many neurological and neuromuscular disorders are results of malfunctions of synaptic connections in the nervous system. The fundamental knowledge on the motor innervation of the muscle obtained from this study should also lead to a better understanding of the causes of these maladies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS023583-10A1
Application #
2264883
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1986-04-01
Project End
1998-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
10
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Zhao, Xiaotao T; Qian, Yueping K; Chan, Ariel W S et al. (2007) Regulation of ACh receptor clustering by the tyrosine phosphatase Shp2. Dev Neurobiol 67:1789-801
Madhavan, Raghavan; Zhao, Xiaotao T; Reynolds, Albert B et al. (2006) Involvement of p120 catenin in myopodial assembly and nerve-muscle synapse formation. J Neurobiol 66:1511-27
Madhavan, Raghavan; Zhao, Xiaotao T; Ruegg, Markus A et al. (2005) Tyrosine phosphatase regulation of MuSK-dependent acetylcholine receptor clustering. Mol Cell Neurosci 28:403-16
Madhavan, Raghavan; Peng, H Benjamin (2005) Molecular regulation of postsynaptic differentiation at the neuromuscular junction. IUBMB Life 57:719-30
Peng, H Benjamin; Yang, Jie-Fei; Dai, Zhengshan et al. (2003) Differential effects of neurotrophins and schwann cell-derived signals on neuronal survival/growth and synaptogenesis. J Neurosci 23:5050-60
Madhavan, Raghavan; Peng, H Benjamin (2003) A synaptic balancing act: local and global signaling in the clustering of ACh receptors at vertebrate neuromuscular junctions. J Neurocytol 32:685-96
Madhavan, Raghavan; Zhao, Xiaotao T; Chan, Frances et al. (2003) The involvement of calcineurin in acetylcholine receptor redistribution in muscle. Mol Cell Neurosci 23:587-99
Dai, Z; Luo, X; Xie, H et al. (2000) The actin-driven movement and formation of acetylcholine receptor clusters. J Cell Biol 150:1321-34
Peng, H B; Xie, H; Rossi, S G et al. (1999) Acetylcholinesterase clustering at the neuromuscular junction involves perlecan and dystroglycan. J Cell Biol 145:911-21
Fu, A K; Smith, F D; Zhou, H et al. (1999) Xenopus muscle-specific kinase: molecular cloning and prominent expression in neural tissues during early embryonic development. Eur J Neurosci 11:373-82

Showing the most recent 10 out of 40 publications