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The Journal of Neuroscience, September 24, 2008, 28(39):9599-9609; doi:10.1523/JNEUROSCI.2589-08.2008

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Development/Plasticity/Repair
Schwann Cells Promote Synaptogenesis at the Neuromuscular Junction via Transforming Growth Factor-β1

Zhihua Feng and Chien-Ping Ko

Department of Biological Sciences, Section of Neurobiology, University of Southern California, Los Angeles, California 90089-2520

Correspondence should be addressed to Dr. Chien-Ping Ko, Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089-2520. Email: cko{at}usc.edu

Recent studies suggest that glial cells actively participate in the formation, function, maintenance, and repair of the chemical synapse. However, the molecular mechanisms of glia–synapse interactions are largely unknown. We have shown previously that Schwann cell-conditioned medium (SC-CM) promotes synaptogenesis in Xenopus nerve–muscle cocultures. The present study aimed to identify the synaptogenic molecules in SC-CM. Combining biochemical approaches and in vitro bioassays, we found that SC-CM contains transforming growth factor (TGF)-β1, which is expressed in Schwann cells both in vivo and in vitro. Similar to SC-CM, TGF-β1 doubled the size of acetylcholine receptor (AChR) clusters at nerve–muscle contacts and significantly increased the percentage of nerve–muscle contacts that show AChR clusters to 60%, compared with 20% seen in control cultures. The synaptogenic effects of SC-CM were abolished if SC-CM was immunodepleted of TGF-β1 or if the latency-associated protein or a TGF-β1 receptor kinase inhibitor was added to block the bioactivity of TGF-β1. Similar to frog SC-CM, mammalian SC-CM also showed synaptogenic effects, which were prevented by immunodepletion of TGF-β1. TGF-β1 upregulated agrin expression in spinal neurons, which could explain the increase in AChR clusters in cultures treated with SC-CM. These results suggest that Schwann cells express TGF-β1, which is both sufficient and necessary for mediating the synapse-promoting effects of Schwann cells at the developing neuromuscular junction. Schwann cell-derived TGF-β1 thus joins other astrocyte-derived synaptogenic factors in further strengthening the emerging concept that glial cells contribute to synaptogenesis in both the PNS and the CNS.

Key words: agrin; glia; neuromuscular junctions; Schwann cell; synaptogenesis; TGF-β1

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Received June 7, 2008; revised July 19, 2008; accepted Aug. 14, 2008.

Correspondence should be addressed to Dr. Chien-Ping Ko, Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089-2520. Email: cko{at}usc.edu

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