title: BMP4 is a peripherally-derived factor for motor neurons and attenuates glutamate-induced excitotoxicity in vitro.
abstract: Bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta (TGF-β) superfamily, have been shown to play important roles in the nervous system, including neuronal survival and synaptogenesis. However, the physiological functions of BMP signaling in the mammalian neuromuscular system are not well understood. In this study, we found that proteins of the type II bone morphogenetic receptors (BMPRII) were detected at the neuromuscular junction (NMJ), and one of its ligands, BMP4, was expressed by Schwann cells and skeletal muscle fibers. In double-ligated nerves, BMP4 proteins accumulated at the proximal and distal portions of the axons, suggesting that Schwann cell- and muscle fiber-derived BMP4 proteins were anterogradely and retrogradely transported by motor neurons. Furthermore, BMP4 mRNA was down-regulated in nerves but up-regulated in skeletal muscles following nerve ligation. The motor neuron-muscle interactions were also demonstrated using differentiated C2C12 muscle cells and NG108-15 neurons in vitro. BMP4 mRNA and immunoreactivity were significantly up-regulated in differentiated C2C12 muscle cells when the motor neuron-derived factor, agrin, was present in the culture. Peripherally-derived BMP4, on the other hand, promotes embryonic motor neuron survival and protects NG108-15 neurons from glutamate-induced excitotoxicity. Together, these data suggest that BMP4 is a peripherally-derived factor that may regulate the survival of motor neurons.
authors.affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Chou
authors.forename: Dar-Ming
authors.initials: DM
authors.lastname: Lai
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Huang
authors.forename: Ian S
authors.initials: IS
authors.lastname: McLennan
authors.forename: Horng-Dar
authors.initials: HD
authors.lastname: Wang
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Wang
mesh_terms: D018171:Agrin / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000633:toxicity*; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018171:Agrin; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D008024:Ligands; D012333:RNA, Messenger; D018698:Glutamic Acid; D052006:Bone Morphogenetic Protein Receptors, Type II