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Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling

2010; Nature Portfolio; Volume: 14; Issue: 1 Linguagem: Inglês

10.1038/nn.2689

1546-1726

Christian B. Vægter, Pernille Jansen, Anja W. Fjorback, Simon Glerup, Sune Skeldal, Mads Kjølby, Mette Richner, Bettina Erdmann, Jens R. Nyengaard, Lino Tessarollo, Gary R. Lewin, Thomas E. Willnow, Moses V. Chao, Anders Nykjær,

Neurogenesis and neuroplasticity mechanisms

The receptor sortilin has been implicated in pro-apoptotic signaling of proneurotrophins. In this study, the authors uncover another role for sortilin in neurotrophin signaling: it interacts with Trk family receptors to promote their anterograde transport to nerve endings, thereby enhancing neurotrophin-dependent cell survival. 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 p75NTR 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.