Schwann cells promote synaptogenesis at the neuromuscular junction via transforming growth factor-beta1.
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.
Feng
Zhihua
Z
Department of Biological Sciences, Section of Neurobiology, University of Southern California, Los Angeles, California 90089-2520, USA.
Ko
Chien-Ping
CP
D018171:Agrin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002038:Bungarotoxins / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D032342:Muscle Cells / Q000502:physiology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011950:Receptors, Cholinergic / Q000378:metabolism; D012583:Schwann Cells / Q000737:chemistry / Q000502:physiology*; D012584:Sciatic Nerve / Q000166:cytology; D013116:Spinal Cord / Q000166:cytology* / Q000187:drug effects; D016704:Synapsins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D014981:Xenopus
D018171:Agrin; D002038:Bungarotoxins; D017077:Culture Media, Conditioned; D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D016704:Synapsins; D053773:Transforming Growth Factor beta1