An important stage in the development of the nervous system takes place when neuronal processes reach their target cells and form synapses. Pre- and most postsynaptic cells interact and become structured for efficient transfer of information across the synapse. Such structuring is typified by that of the neuromuscular junction in which nerve endings somehow dictate the precise positions of acetylcholine receptors (AChRs) and acetylcholinesterase in the postsynaptic region. The purpose of experiments suggested in this grant proposal is to understand, in molecular terms, how AChRs are localized. This will first involve identifying chemical factors used by neurons to mark the synaptic region. Related factors eventually become localized in the muscle fiber's basal lamina and provide an accessible starting source for their purification. Secondly, the formation of an AChR cluster involves cytoplasmic, possibly cytoskeletal, elements which can be identified by making use of the observation that cells transformed with Rous sarcoma virus (RSV) are unable to cluster AChRs. This suggests that an essential component of AChR clusters is phosphorylated and disrupted by the transforming factor of RSV, pp60src. Finally, AChR clusters become localized above myonuclei and Golgi apparatus following a decrease in the movement of cellular organelles. The manner in which this colocalization occurs, as well as its functional consequences, will be investigated. The proposed experiments should provide information crucial to understanding molecular events which occur during normal synapse formation and synaptic functioning. They should also contribute to an understanding of a variety of neuro-developmental disorders. Finally, these experiments are designed to study a discrete, readily observable aspect of cell function caused by viral transformation and could well contribute to a greater understanding of the transformation process.
| O'Malley, J P; Rubin, L L; Salpeter, M M (1993) Two populations of AChR in rat myotubes have different degradation rates and responses to cAMP. Exp Cell Res 208:44-7 |
