Neuromuscular synapses form following a series of complex interactions between motor neurons, muscle fibers and Schwann cells. Signals provided by motor neurons have a key role in directing the differentiation of the muscle fiber at synaptic sites, and signals provided by muscle fibers have an important role in regulating motor axon growth and differentiation. Agrin, a 200 kD protein synthesized by motor neurons, is a critical synaptic signaling molecule that organizes postsynaptic differentiation by stimulating MuSK, a muscle-specific receptor tyrosine kinase. Mice lacking MuSK fail to form neuromuscular synapses and consequently die at birth due to their failure to move or breathe. MuSK is required for multiple aspects of presynaptic and postsynaptic differentiation, as MuSK mutant mice fail to cluster skeletal muscle-derived proteins, including acetylcholine receptors, to preferentially transcribe acetylcholine receptor genes in synaptic nuclei, and to provide retrograde signals for nerve terminal differentiation. The steps that follow MuSK activation and that lead to neuromuscular synapse formation are poorly understood. Our studies have demonstrated that the juxtamembrane domain of MuSK has a critical role in regulating MuSK signaling and directing synaptic differentiation. Experiments described here are designed to reveal how the MuSK juxtamembrane region regulates synaptic differentiation by identifying and studying the proteins that interact with this critical domain of MuSK. MuSK activation leads to tyrosine phosphorylation of the acetylcholine receptor beta and delta subunits, but the role of acetylcholine receptor tyrosine phosphorylation is not known. Molecular genetic experiments described here are designed to reveal the role that acetylcholine receptor tyrosine phosphorylation may have in synaptic differentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036193-09
Application #
7097939
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Porter, John D
Project Start
1998-02-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
9
Fiscal Year
2006
Total Cost
$391,943
Indirect Cost
Name
New York University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Lee, Jennifer K; Hallock, Peter T; Burden, Steven J (2017) Abelson tyrosine-protein kinase 2 regulates myoblast proliferation and controls muscle fiber length. Elife 6:
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Pérez-García, María J; Burden, Steven J (2012) Increasing MuSK activity delays denervation and improves motor function in ALS mice. Cell Rep 2:497-502
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Gomez, Andrea M; Burden, Steven J (2011) The extracellular region of Lrp4 is sufficient to mediate neuromuscular synapse formation. Dev Dyn 240:2626-33
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Bergamin, Elisa; Hallock, Peter T; Burden, Steven J et al. (2010) The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization. Mol Cell 39:100-9

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