Department of Neurobiology and Behavior, Center for Nervous System Disorders and Program in Neuroscience, Stony Brook University, Stony Brook, NY 11794-5230, USA.
Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):852-7. doi: 10.1073/pnas.1015981108. Epub 2010 Dec 27.
Target-derived neurotrophins use retrogradely transported Trk-signaling endosomes to promote survival and neuronal phenotype at the soma. Despite their critical role in neurotrophin signaling, the nature and molecular composition of these endosomes remain largely unknown, the result of an inability to specifically identify the retrograde signaling entity. Using EGF-bound nanoparticles and chimeric, EGF-binding TrkB receptors, we elucidate Trk-endosomal events involving their formation, processing, retrograde transport, and somal signaling in sympathetic neurons. By comparing retrograde endosomal signaling by Trk to the related but poorly neuromodulatory EGF-receptor, we find that Trk and EGF-receptor endosomes are formed and processed by distinct mechanisms. Surprisingly, Trk and EGF-receptors are both retrogradely transported to the soma in multivesicular bodies. However, only the Trk-multivesicular bodies rely on Pincher-dependent macroendocytosis and processing. Retrograde signaling through Pincher-generated Trk-multivesicular bodies is distinctively refractory to signal termination by lysosomal processing, resulting in sustained somal signaling and neuronal gene expression.
靶源性神经营养因子利用逆行转运的 Trk 信号转导内体促进神经元存活和胞体的表型。尽管它们在神经营养因子信号转导中起着关键作用，但这些内体的性质和分子组成在很大程度上仍然未知，这是由于无法特异性识别逆行信号实体的结果。我们使用 EGF 结合的纳米颗粒和嵌合的 EGF 结合型 TrkB 受体，阐明了涉及交感神经元中它们形成、加工、逆行运输和胞体信号转导的 Trk 内体事件。通过比较 Trk 和相关但神经调节作用差的 EGF 受体的逆行内体信号转导，我们发现 Trk 和 EGF 受体内体的形成和加工是通过不同的机制进行的。令人惊讶的是，Trk 和 EGF 受体都以多泡体的形式逆行转运到胞体。然而，只有 Trk 多泡体依赖 Pincher 依赖性巨胞饮作用和加工。通过 Pincher 产生的 Trk 多泡体进行逆行信号转导对溶酶体加工导致的信号终止具有明显的抗性，导致持续的胞体信号转导和神经元基因表达。
