Synapse formation requires the coordinated synthesis and localization of a unique set of molecules. During development of the neuromuscular junction, a number of specialized proteins are synthesized by muscle cells and localized specifically at synaptic regions. One of these components is the acetylcholine receptor (AchR). One of the mechanisms responsible for localizing the AchR is by restricted transcription to a subset of muscle fiber nuclei at the synaptic region. This synapse- specific gene expression is thought to be induced by neuregulin, a factor which is present in motor neurons. In cultured muscle cells, neuregulin can induce transcription of AchR genes, providing a useful system for analyzing this signaling pathway. In the proposed experiments, the direct interaction of the neuregulin signaling pathway with the promoter of a responsive gene, the AchR epsilon subunit gene, will be examined.
The specific aims of this research are 1) to identify elements in the AchR epsilon promoter which are responsible for neuregulin-inducible expression and for synapse-specific gene expression, and 2) To identify proteins that interact with NRG-response elements in the epsilon promoter. In addition to providing information on development of the neuromuscular synapse, the proposed experiments may also yield insight into other processes which are influenced by neuregulin signaling, such as cellular transformation.
