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 development of this prototypical synapse. In particular, the investigator seeks to unravel cellular and molecular mechanisms that govern the development of the postsynaptic membrane of the neuromuscular junction.
The specific aims are: (1) to understand the interplay between agrin, heparin-binding growth factors and receptor tyrosine kinases in the signaling of the postsynaptic development; (2) to examine the role of the postsynaptic actin-based cytoskeleton in serving as a scaffolding for the assembly and the stabilization of postsynaptic specializations; and (3) to study the mechanism for the clustering of acetylcholinesterase in the postsynaptic membrane and the cellular machinery for generating the transmembrane macromolecular complex at the neuromuscular junction. 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, immunocytochemistry, protein biochemistry, molecular biology and electrophysiology, will be used to observe the development of the neuromuscular junction 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 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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