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.
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