The formation of neuromuscular synapses requires a series of inductive interactions between the developing motor neuron and muscle fiber, culminating in the formation of a highly specialized nerve terminal and a highly differentiated postsynaptic membrane. Agrin, a protein secreted by motor neurons and deposited into the basal lamina at the synapse, is a critical signal for synapse formation since it is responsible for clustering postsynaptic proteins, including the acetylcholine receptor (AChR), at the neuromuscular synapse. MuSK, a receptor tyrosine kinase that is localized to neuromuscular synapses, is required for agrin- mediated signalling and appears to be a component of an agrin receptor complex. MuSK, however, does not bind agrin, and these results have led to the idea that another membrane protein binds agrin and activates MuSK. I propose to identify the functional agrin receptor that cooperates with MuSK to organize the postsynaptic membrane at developing neuromuscular synapses.
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