Neurotrophin-3 regulates synapse development by modulating TrkC-PTPσ synaptic adhesion and intracellular signaling pathways

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Title
Neurotrophin-3 regulates synapse development by modulating TrkC-PTPσ synaptic adhesion and intracellular signaling pathways
Author(s)
Kyung Ah Han; Doyeon Woo; Seungjoon Kim; Gayoung Choii; Sangmin Jeon; Seung Youn Won; Ho Min Kim; Won Do Heo; Ji Won Um; Jaewon Ko
Publication Date
2016-04
Journal
JOURNAL OF NEUROSCIENCE, v.36, no.17, pp.4816 - 4831
Publisher
SOC NEUROSCIENCE
Abstract
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. © 2016 the authors
URI
https://pr.ibs.re.kr/handle/8788114/2610
ISSN
0270-6474
Appears in Collections:
Center for Cognition and Sociality(인지 및 사회성 연구단) > Journal Papers (저널논문)
Files in This Item:
201604 J Neurosci.pdfDownload

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