title: ProBDNF and mature BDNF as punishment and reward signals for synapse elimination at mouse neuromuscular junctions.
abstract: During development, mammalian neuromuscular junctions (NMJs) transit from multiple-innervation to single-innervation through axonal competition via unknown molecular mechanisms. Previously, using an in vitro model system, we demonstrated that the postsynaptic secretion of pro-brain-derived neurotrophic factor (proBDNF) stabilizes or eliminates presynaptic axon terminals, depending on its proteolytic conversion at synapses. Here, using developing mouse NMJs, we obtained in vivo evidence that proBDNF and mature BDNF (mBDNF) play roles in synapse elimination. We observed that exogenous proBDNF promoted synapse elimination, whereas mBDNF infusion substantially delayed synapse elimination. In addition, pharmacological inhibition of the proteolytic conversion of proBDNF to mBDNF accelerated synapse elimination via activation of p75 neurotrophin receptor (p75(NTR)). Furthermore, the inhibition of both p75(NTR) and sortilin signaling attenuated synapse elimination. We propose a model in which proBDNF and mBDNF serve as potential "punishment" and "reward" signals for inactive and active terminals, respectively, in vivo.
authors.affiliation: Section on Neural Development and Plasticity, National Institute of Child Health and Human Development, and Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, Maryland 20892-3714, USA. shawn.je@duke-nus.edu.sg
authors.forename: H Shawn
authors.initials: HS
authors.lastname: Je
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ji
authors.forename: Srilatha
authors.initials: S
authors.lastname: Potluri
authors.forename: Xiu-Qing
authors.initials: XQ
authors.lastname: Fu
authors.forename: Zhen-Ge
authors.initials: ZG
authors.lastname: Luo
authors.forename: Guhan
authors.initials: G
authors.lastname: Nagappan
authors.forename: Jia Pei
authors.initials: JP
authors.lastname: Chan
authors.forename: Barbara
authors.initials: B
authors.lastname: Hempstead
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Son
authors.forename: Bai
authors.initials: B
authors.lastname: Lu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009469:Neuromuscular Junction / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology
chemical_list: C582212:1NMPP1 compound; D019208:Brain-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D011498:Protein Precursors; D011720:Pyrazoles; D011743:Pyrimidines; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D020813:Receptor, trkB