Motor neurons and skeletal muscle exchange signals to ensure differentiation of presynaptic and postsynaptic membranes at the neuromuscular synapse. Agrin, provided by motor neurons, binds to Lrp4 in muscle, which stimulates association between Lrp4 and MuSK, a receptor tyrosine kinase, leading to MuSK activation. Tyrosine-phosphorylated, activated MuSK initiates a pathway that anchors essential postsynaptic proteins, including acetylcholine receptors and Lrp4, in the postsynaptic membrane and induces expression of the genes encoding these postsynaptic proteins in subsynaptic nuclei. Once clustered by MuSK signaling, Lrp4 functions as a direct retrograde signal to motor nerve terminals to induce presynaptic differentiation. One aim of my thesis has been to identify and study the motor neuron receptor that binds and responds to Lrp4 to induce presynaptic differentiation. Here, I describe two family members that are candidate Lrp4-receptors (Lrp4-Rs) and provide evidence that these receptors have an important role in neuromuscular synapse formation. First, I show that Lrp4-expressing cells induce presynaptic differentiation in motor neurons derived from ES cells but not in mutant ES cell-derived motor neurons deficient in the Lrp4-Rs. Second, I show that at least one of the Lrp4-Rs is concentrated at the neuromuscular synapse. Third, mice deficient in the Lrp4-Rs display defects in synapse formation, suggesting that these Lrp4-Rs respond to Lrp4 to regulate presynaptic differentiation. In the second half of my thesis work, I describe experiments to test whether boosting this retrograde signaling pathway, by increasing MuSK activity, might keep motor nerve terminals attached to muscle in denervating diseases, such as Amyotrophic Lateral Sclerosis (ALS). In ALS, motor nerve terminals detach from muscle and subsequently undergo cell death, together leading to progressive motor weakness and ultimately respiratory paralysis. I show that increasing MuSK activity, using an agonist antibody to MuSK, decreases muscle denervation, improves motor system output, reduces motor neuron cell death, and extends the lifespan of SOD1 G93A mice, an aggressive model for ALS. These results reveal a novel therapeutic strategy for ALS, which targets a key signaling pathway for maintaining the attachment of nerve terminals to muscle.
|Commitee:||Chao, Moses, Ringstad, Niels, Sanes, Joshua, Treisman, Jessica|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 79/12(E), Dissertation Abstracts International|
|Keywords:||Amyotrophic lateral sclerosis, Lrp4, Motor neuron, MuSK, Neuromuscular disease, Neuromuscular junction|
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