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Published online
doi:10.1083/jcb.200610060
The Journal of Cell Biology, Vol. 177, No. 6, 1077-1089
The Rockefeller University Press, 0021-9525 $30.00
© Lu et al.
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Article

Regulation of synaptic growth and maturation by a synapse-associated E3 ubiquitin ligase at the neuromuscular junction



Zhonghua Lu1, Hyun-Soo Je3, Paul Young1, Jimmy Gross1, Bai Lu3, and Guoping Feng1,2

1 Department of Neurobiology and 2 Department of Pathology, Duke University Medical Center, Durham, NC 27710
3 Section on Neural Development and Plasticity, National Institute of Child Health and Human Development (NICHD) and Genes, Cognition and Psychosis Program (GCAP), National Institute of Mental Health (NIMH), National Institutes of Health, Bethesda, MD 20892

Correspondence to Guoping Feng: feng{at}neuro.duke.edu

The ubiquitin–proteasome pathway has been implicated in synaptic development and plasticity. However, mechanisms by which ubiquitination contributes to precise and dynamic control of synaptic development and plasticity are poorly understood. We have identified a PDZ domain containing RING finger 3 (PDZRN3) as a synapse-associated E3 ubiquitin ligase and have demonstrated that it regulates the surface expression of muscle-specific receptor tyrosine kinase (MuSK), the key organizer of postsynaptic development at the mammalian neuromuscular junction. PDZRN3 binds to MuSK and promotes its ubiquitination. Regulation of cell surface levels of MuSK by PDZRN3 requires the ubiquitin ligase domain and is mediated by accelerated endocytosis. Gain- and loss-of-function studies in cultured myotubes show that regulation of MuSK by PDZRN3 plays an important role in MuSK-mediated nicotinic acetylcholine receptor clustering. Furthermore, overexpression of PDZRN3 in skeletal muscle of transgenic mice perturbs the growth and maturation of the neuromuscular junction. These results identify a synapse-associated E3 ubiquitin ligase as an important regulator of MuSK signaling.

Abbreviations used in this paper: AChR, nicotinic acetylcholine receptor; MLC, myosin light chain; MuSK, muscle-specific receptor tyrosine kinase; NMJ, neuromuscular junction; PDZRN3, PDZ domain containing RING finger 3; siRNA, small interfering RNA.


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