Agrin/MuSK Signaling at the Neuromuscular Synapse

Neuromuscular synapses form in a series of steps that involve an exchange of signals between the growth cone of a motor neuron and a developing skeletal muscle cell. As a result the postsynaptic muscle membrane is biochemically different from the rest of the muscle: proteins important for synaptic function like the receptors for the neurotransmitter acetylcholine are concentrated at synaptic sites. Agrin, a protein which is synthesized by motor neurons, and MuSK, a receptor tyrosine kinase selectively expressed in skeletal muscle, are key players in the formation of the neuromuscular synapse. Agrin is deposited into the basal lamina by motor neurons and activates MuSK by a yet unknown mechanism. Activation of MuSK leads to the clustering of acetylcholine receptors, a process critical for synaptic function. The exact events that are downstream from MuSK activation and that lead to the clustering of proteins at synapses are unknown. With the proposed experiments I will continue and extend studies to identify and characterize molecules that interact with MuSK and that are necessary for the agrin-induced signal transduction pathway leading to the redistribution of synaptic proteins including acetylcholine receptors. In addition, genetic studies indicate that retrograde signals are produced or organized by muscle fibers following MuSK activation, which induce the differentiation of the presynaptic nerve terminal. It is thought that MuSK activation at the right time and in the right place plays a crictical role in this process. I will use transgenic mice that express MuSK in a spatial and temporal manner different from endogenous MuSK to study presynaptic nerve terminal differentiation.

Neuromuscular synapses form in a series of steps that involve an exchange of signals between the growth cone of a motor neuron and a developing skeletal muscle cell. As a result the postsynaptic muscle membrane is biochemically different from the rest of the muscle: proteins important for synaptic function like the receptors for the neurotransmitter acetylcholine are concentrated at synaptic sites. Agrin, a protein which is synthesized by motor neurons, and MuSK, a receptor tyrosine kinase selectively expressed in skeletal muscle, are key players in the formation of the neuromuscular synapse. Agrin is deposited into the basal lamina by motor neurons and activates MuSK by a yet unknown mechanism. Activation of MuSK leads to the clustering of acetylcholine receptors, a process critical for synaptic function. The exact events that are downstream from MuSK activation and that lead to the clustering of proteins at synapses are unknown. With the proposed experiments I will continue and extend studies to identify and characterize molecules that interact with MuSK and that are necessary for the agrin-induced signal transduction pathway leading to the redistribution of synaptic proteins including acetylcholine receptors. In addition, genetic studies indicate that retrograde signals are produced or organized by muscle fibers following MuSK activation, which induce the differentiation of the presynaptic nerve terminal. It is thought that MuSK activation at the right time and in the right place plays a crictical role in this process. I will use transgenic mice that express MuSK in a spatial and temporal manner different from endogenous MuSK to study presynaptic nerve terminal differentiation.