The Lundbeck Foundation Research Center MIND, Department of Medical Biochemistry, Aarhus University, Aarhus, Denmark.
Nat Neurosci. 2011 Jan;14(1):54-61. doi: 10.1038/nn.2689. Epub 2010 Nov 21.
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.
靶源性神经营养因子与神经末梢处的 Trk 受体结合对于刺激神经元存活、分化、神经支配和突触可塑性是必需的。由于胞体与神经末梢之间的距离较大，因此有效的顺行 Trk 运输对于 Trk 的突触易位和信号转导至关重要。负责这种运输的机制仍知之甚少。在这里，我们表明分拣受体 sortilin 与 TrkA、TrkB 和 TrkC 相互作用，并能够促进它们的顺行轴突运输，从而增强神经营养因子信号。缺乏 sortilin 的培养 DRG 神经元在受到 NGF 刺激时显示出 MAP 激酶信号转导减弱和突起生长减少。此外，sortilin 的缺乏显著加重了 p75(NTR) 敲除小鼠中存在的 TrkA、TrkB 和 TrkC 表型，并导致 TrkA 杂合子小鼠的胚胎致死率和交感神经病变增加。我们的研究结果表明 sortilin 作为 Trk 的顺行运输受体和神经营养因子诱导的神经元存活的正调节剂发挥作用。
