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.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Animals, Newborn
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Axons / metabolism
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Brain-Derived Neurotrophic Factor / deficiency
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Brain-Derived Neurotrophic Factor / physiology*
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Female
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / genetics*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Nerve Tissue Proteins / metabolism
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Neuromuscular Junction / drug effects
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Neuromuscular Junction / growth & development
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Neuromuscular Junction / metabolism*
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism
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Presynaptic Terminals / metabolism
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Protein Kinase Inhibitors / pharmacology
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Protein Precursors / physiology*
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Pyrazoles / pharmacology
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Pyrimidines / pharmacology
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Receptor, trkB / genetics
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Receptor, trkB / metabolism
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Receptors, Nerve Growth Factor / deficiency
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Spinal Cord / cytology
Substances
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1NMPP1 compound
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Brain-Derived Neurotrophic Factor
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Nerve Tissue Proteins
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Protein Kinase Inhibitors
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Protein Precursors
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Pyrazoles
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Pyrimidines
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Receptors, Nerve Growth Factor
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Ngfr protein, mouse
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Receptor, trkB