The development and maintenance of the neuromuscular junction - the place where nerve and muscle communicate - is critical to our proper functioning. Research in this area has obvious implications for neuromuscular disorders such as myasthenia gravis, but also provides crucial information about the way that neural circuits are formed. Pre- and post-synaptic signals at the NMJ and other synapses lead to receptor clustering and strengthened connections, creating meaningful circuitry from what would otherwise be the equivalent of a tangle of wires. This project investigates the signaling cascade that leads to acetylcholine receptor clustering in the post-synaptic muscle cell. Specifically, we seek to define the means by which agrin stimulation is linked to non-receptor Abl tyrosine kinase activity. We will determine whether agrin stimulation leads to increased Abl activity and promotes association with the agrin receptor MUSK. We will also elucidate the mechanisms by which Abl mediates receptor clustering, including an investigation of whether Abl activity is partially mediated by Rapsyn, a protein known to directly affect receptor clustering.
