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Originally published In Press as doi:10.1074/jbc.M106116200 on January 14, 2002

J. Biol. Chem., Vol. 277, Issue 12, 10614-10625, March 22, 2002
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Regulation of Neuromuscular Synapse Development by Glial Cell Line-derived Neurotrophic Factor and Neurturin*

Chang-Yu WangDagger §, Feng YangDagger , Xiang-Ping HeDagger , Hyun-Soo JeDagger §, Jian-Zheng ZhouDagger , Kary EckermannDagger , David KawamuraDagger , Linyin FengDagger ||, Liya Shen**, and Bai LuDagger Dagger Dagger

From the Dagger  Unit on Synapse Development and Plasticity, NICHD, National Institutes of Health, Bethesda, Maryland 20892, the § Genetics Graduate Program, George Washington University, Washington, D.C. 20052, the ** Laboratory of Cellular Carcinogenesis and Tumor Promotion, NCI, National Institutes of Health, Bethesda, Maryland 20892, and the || Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China 200031

Glial cell line-derived neurotrophic factor (GDNF) is known for its potent effect on neuronal survival, but its role in the development and function of synapses is not well studied. Using Xenopus nerve-muscle co-cultures, we show that GDNF and its family member neurturin (NRTN) facilitate the development of the neuromuscular junction (NMJ). Long-term application of GDNF significantly increased the total length of neurites in the motoneurons. GDNF also caused an increase in the number and the size of synaptic vesicle clustering, as demonstrated by synaptobrevin-GFP fluorescent imaging, and FM dye staining. Electrophysiological experiments revealed two effects of GDNF on synaptic transmission at NMJ. First, GDNF markedly increased the frequency of spontaneous transmission and decreased the variability of evoked transmission, suggesting an enhancement of transmitter secretion. Second, GDNF elicited a small increase in the quantal size, without affecting the average rise and decay times of synaptic currents. Imaging analysis showed that the size of acetylcholine receptor clusters at synapses increased in muscle cells overexpressing GDNF. Neurturin had very similar effects as GDNF. These results suggest that GDNF and NRTN are new neuromodulators that regulate the development of the neuromuscular synapse through both pre- and postsynaptic mechanisms.


* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to the results of this work.

Dagger Dagger To whom correspondence should be addressed: Unit on Synapse Development and Plasticity, NICHD, National Institutes of Health, Bldg. 49, Rm. 6A-80, 49 Convent Dr., MSC4480, Bethesda, MD 20892-4480. Tel.: 301-435-2970; Fax: 301-496-1777; E-mail: lub@codon.nih.gov.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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