Schwann cells promote synaptogenesis at the neuromuscular junction via transforming growth factor-beta1

J Neurosci. 2008 Sep 24;28(39):9599-609. doi: 10.1523/JNEUROSCI.2589-08.2008.


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)-beta1, which is expressed in Schwann cells both in vivo and in vitro. Similar to SC-CM, TGF-beta1 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 approximately 60%, compared with approximately 20% seen in control cultures. The synaptogenic effects of SC-CM were abolished if SC-CM was immunodepleted of TGF-beta1 or if the latency-associated protein or a TGF-beta1 receptor kinase inhibitor was added to block the bioactivity of TGF-beta1. Similar to frog SC-CM, mammalian SC-CM also showed synaptogenic effects, which were prevented by immunodepletion of TGF-beta1. TGF-beta1 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-beta1, which is both sufficient and necessary for mediating the synapse-promoting effects of Schwann cells at the developing neuromuscular junction. Schwann cell-derived TGF-beta1 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Agrin / genetics
  • Agrin / metabolism
  • Animals
  • Animals, Newborn
  • Bungarotoxins / metabolism
  • Cells, Cultured
  • Coculture Techniques / methods
  • Culture Media, Conditioned / pharmacology
  • Dose-Response Relationship, Drug
  • Embryo, Nonmammalian
  • Enzyme-Linked Immunosorbent Assay / methods
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Muscle Cells / physiology*
  • Neuromuscular Junction / drug effects
  • Neuromuscular Junction / physiology*
  • Neurons / drug effects
  • Neurons / physiology*
  • RNA, Messenger / metabolism
  • Rats
  • Receptors, Cholinergic / metabolism
  • Schwann Cells / chemistry
  • Schwann Cells / physiology*
  • Sciatic Nerve / cytology
  • Spinal Cord / cytology*
  • Spinal Cord / drug effects
  • Synapsins / metabolism
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism
  • Transforming Growth Factor beta1 / pharmacology*
  • Xenopus


  • Agrin
  • Bungarotoxins
  • Culture Media, Conditioned
  • RNA, Messenger
  • Receptors, Cholinergic
  • Synapsins
  • Transforming Growth Factor beta1