Niu Yang, Dai Zhonghua, Liu Wenxue, Zhang Cheng, Yang Yanrui, Guo Zhenzhen, Li Xiaoyu, Xu Chenchang, Huang Xiahe, Wang Yingchun, Shi Yun S, Liu Jia-Jia
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
Elife. 2017 Jan 30;6:e20991. doi: 10.7554/eLife.20991.
SNX6 is a ubiquitously expressed PX-BAR protein that plays important roles in retromer-mediated retrograde vesicular transport from endosomes. Here we report that CNS-specific knockout mice exhibit deficits in spatial learning and memory, accompanied with loss of spines from distal dendrites of hippocampal CA1 pyramidal cells. SNX6 interacts with Homer1b/c, a postsynaptic scaffold protein crucial for the synaptic distribution of other postsynaptic density (PSD) proteins and structural integrity of dendritic spines. We show that SNX6 functions independently of retromer to regulate distribution of Homer1b/c in the dendritic shaft. We also find that Homer1b/c translocates from shaft to spines by protein diffusion, which does not require SNX6. Ablation of SNX6 causes reduced distribution of Homer1b/c in distal dendrites, decrease in surface levels of AMPAR and impaired AMPAR-mediated synaptic transmission. These findings reveal a physiological role of SNX6 in CNS excitatory neurons.
分选连接蛋白6（SNX6）是一种在全身广泛表达的PX-BAR蛋白，在内体的逆转录酶介导的逆行囊泡运输中发挥重要作用。在此，我们报告中枢神经系统特异性敲除小鼠在空间学习和记忆方面表现出缺陷，同时伴有海马CA1锥体细胞远端树突棘的丢失。SNX6与Homer1b/c相互作用，Homer1b/c是一种突触后支架蛋白，对其他突触后致密物（PSD）蛋白的突触分布和树突棘的结构完整性至关重要。我们发现，SNX6独立于逆转录酶发挥作用，以调节Homer1b/c在树突干中的分布。我们还发现，Homer1b/c通过蛋白质扩散从树突干转移到树突棘，这一过程不需要SNX6。敲除SNX6会导致Homer1b/c在远端树突中的分布减少、AMPA受体表面水平降低以及AMPA受体介导的突触传递受损。这些发现揭示了SNX6在中枢神经系统兴奋性神经元中的生理作用。
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