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Title: 轴突起始段胞浆屏障与神经元蛋白的极性分布
Author: 宋瑷宏
Degree Level: 博士
Issued Date: 2008-05-08
Degree Grantor: 中国科学院上海生命科学研究院
Place of Degree Grantor: 上海生命科学研究院
Supervisor: 段树民
Keyword: 神经元极性 ; 轴突起始段 ; 屏障 ; 转运 ; 微丝蛋白 ; 驱动蛋白
Alternative Title: A selective filter for cytoplasmic transport in the axon initial segment
Major: 神经生物学
Abstract: 神经元(神经细胞)在结构和功能上均具有极性(Polarity),即其有两个完全不同的组成部分-胞体树突部分和轴突部分。胞体和树突负责接受和处理电信号,轴突则通过产生和发放动作电位来传递信息。这两部分功能的差异是其蛋白组成不同造成的。蛋白质根据其功能的不同,特异的分布到轴突或者树突。蛋白质的极性分布如何形成以及维持?这是神经生物学领域的重要问题。轴突起始段(Axon initial segment, AIS)处于两个部分的交界位置,以其重要和神秘,引起了我们的关注。我们发现培养神经元在极性建立后的两天内,AIS胞浆里出现一个物理性屏障,阻碍了大分子物质(70kD Dextran和BSA)扩散进轴突,允许小分子物质(10kD Dextran)和小分子胞浆蛋白(GFP)通过。该屏障对膜蛋白转运囊泡的微管依赖性主动运输也有影响,能够阻碍KIF17驱动的树突膜蛋白NR2B进入轴突,允许KIF5驱动的突触囊泡膜蛋白VAMP2通过。驱动蛋白(Kinesin)头端提供的驱动力的强弱是膜蛋白能否通过AIS胞浆屏障的主要原因,含KIF5头和KIF17尾的嵌合驱动蛋白可以将NR2B带入轴突,而表达KIF17头和KIF5 尾的嵌合驱动蛋白,VAMP2在轴突的分布明显降低。用Latrunculin A (LatA)解聚微丝蛋白网(Filament-Actin, F-actin)能够破坏AIS胞浆屏障。以上结果表明AIS存在一个由F-Actin构成的胞浆屏障,对蛋白的自由扩散和主动运输均有选择性阻碍作用,从而维持神经元蛋白的极性转运和分布。
English Abstract: Distinct components are selectively transported and segregated into somatodendritic and axonal domains of the polarized neuron, but how such segregation is achieved remains largely unclear. We found that a filamentous actin based selective filter emerges in the cytoplasm of the axon initial segment (AIS) within two days after axon differentiation in cultured hippocampal neurons, impeding the diffusional spread of large macromolecules. This cytoplasmic filter also imposes a selective impediment of microtubule-based active transport: Dendrite-targeting KIF17-driven vesicular carriers containing the N-methyl-D-aspartate receptor (NMDA) receptor subunit NR2B were prevented from entering the axon, whereas axonal entry of KIF5-driven carriers containing synaptic vesicle membrane protein VAMP2 were much less affected. Over-expression of the chimeric KIF17 and KIF5, in which the cargo- and microtubule-binding domains were switched, resulted in axonal entry of NR2B and exclusion of VAMP2 from the axon, suggesting that KIF5 motor is responsible for driving VAMP2 carriers through the AIS filter. Thus selective filtering at the AIS contributes to preferential trafficking and segregation cellular components in the polarized neuron.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2366
Appears in Collections:神经所(总)_学位论文

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Recommended Citation:
轴突起始段胞浆屏障与神经元蛋白的极性分布.宋瑷宏[d].中国科学院上海生命科学研究院,2008.20-25
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