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Neurotrophin-3 Regulates Synapse Development by Modulating TrkC-PTPσ Synaptic Adhesion and Intracellular Signaling Pathways.

 Kyung Ah Han  ;  Doyeon Woo  ;  Seungjoon Kim  ;  Gayoung Choii  ;  Sangmin Jeon  ;  Seoung Youn Won  ;  Ho Min Kim  ;  Won Do Heo  ;  Ji Won Um  ;  Jaewon Ko 
 JOURNAL OF NEUROSCIENCE, Vol.36(17) : 4816-4831, 2016 
Journal Title
Issue Date
Animals ; Cell Differentiation/drug effects ; Cells, Cultured ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Hippocampus ; Neurons/physiology ; Neurotrophin 3/secretion* ; Protein Binding ; Rats ; Receptor, trkC/metabolism* ; Receptor-Like Protein Tyrosine Phosphatases, Class 2/genetics ; Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism* ; Signal Transduction/drug effects ; Synapses/metabolism* ; Synapses/physiology
PTPσ ; TrkC ; excitatory synapse ; neurotrophin-3 ; synaptic cell adhesion
Neurotrophin-3 (NT-3) is a secreted neurotrophic factor that binds neurotrophin receptor tyrosine kinase C (TrkC), which in turn binds to presynaptic protein tyrosine phosphatase σ (PTPσ) to govern excitatory synapse development. However, whether and how NT-3 cooperates with the TrkC-PTPσ synaptic adhesion pathway and TrkC-mediated intracellular signaling pathways in rat cultured neurons has remained unclear. Here, we report that NT-3 enhances TrkC binding affinity for PTPσ. Strikingly, NT-3 treatment bidirectionally regulates the synaptogenic activity of TrkC: at concentrations of 10-25 ng/ml, NT-3 further enhanced the increase in synapse density induced by TrkC overexpression, whereas at higher concentrations, NT-3 abrogated TrkC-induced increases in synapse density. Semiquantitative immunoblotting and optogenetics-based imaging showed that 25 ng/ml NT-3 or light stimulation at a power that produced a comparable level of NT-3 (6.25 μW) activated only extracellular signal-regulated kinase (ERK) and Akt, whereas 100 ng/ml NT-3 (light intensity, 25 μW) further triggered the activation of phospholipase C-γ1 and CREB independently of PTPσ. Notably, disruption of TrkC intracellular signaling pathways, extracellular ligand binding, or kinase activity by point mutations compromised TrkC-induced increases in synapse density. Furthermore, only sparse, but not global, TrkC knock-down in cultured rat neurons significantly decreased synapse density, suggesting that intercellular differences in TrkC expression level are critical for its synapse-promoting action. Together, our data demonstrate that NT-3 is a key factor in excitatory synapse development that may direct higher-order assembly of the TrkC/PTPσ complex and activate distinct intracellular signaling cascades in a concentration-dependent manner to promote competition-based synapse development processes. SIGNIFICANCE STATEMENT: In this study, we present several lines of experimental evidences to support the conclusion that neurotrophin-3 (NT-3) modulates the synaptic adhesion pathway involving neurotrophin receptor tyrosine kinase C (TrkC) and presynaptic protein tyrosine phosphatase σ (PTPσ) in a bidirectional manner at excitatory synapses. NT-3 acts in concentration-independent manner to facilitate TrkC-mediated presynaptic differentiation, whereas it acts in a concentration-dependent manner to exert differential effects on TrkC-mediated organization of postsynaptic development. We further investigated TrkC extracellular ligand binding, intracellular signaling pathways, and kinase activity in NT-3-induced synapse development. Last, we found that interneuronal differences in TrkC levels regulate the synapse number. Overall, these results suggest that NT-3 functions as a positive modulator of synaptogenesis involving TrkC and PTPσ.
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1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Um, Ji Won(엄지원)
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