Sortilin Associates with Trk Receptors to Enhance Anterograde Transport and Neurotrophin Signaling

Overview

Journal Nat Neurosci

Date 2010 Nov 25

PMID 21102451

Citations 87

Authors

Christian B Vaegter

Pernille Jansen

Anja W Fjorback

Simon Glerup

Sune Skeldal

Mads Kjolby

Mette Richner

Bettina Erdmann

Jens R Nyengaard

Lino Tessarollo

Gary R Lewin

Thomas E Willnow

Moses V Chao

Anders Nykjaer

Affiliations

Soon will be listed here.

Abstract

Binding of target-derived neurotrophins to Trk receptors at nerve terminals is required to stimulate neuronal survival, differentiation, innervation and synaptic plasticity. The distance between the soma and nerve terminal is great, making efficient anterograde Trk transport critical for Trk synaptic translocation and signaling. The mechanism responsible for this trafficking remains poorly understood. Here we show that the sorting receptor sortilin interacts with TrkA, TrkB and TrkC and enables their anterograde axonal transport, thereby enhancing neurotrophin signaling. Cultured DRG neurons lacking sortilin showed blunted MAP kinase signaling and reduced neurite outgrowth upon stimulation with NGF. Moreover, deficiency for sortilin markedly aggravated TrkA, TrkB and TrkC phenotypes present in p75(NTR) knockouts, and resulted in increased embryonic lethality and sympathetic neuropathy in mice heterozygous for TrkA. Our findings demonstrate a role for sortilin as an anterograde trafficking receptor for Trk and a positive modulator of neurotrophin-induced neuronal survival.

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