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Title: TrkB介导的蛋白异戊二烯基转移酶激活促进神经元树突发育
Author: 周秀萍
Degree Level: 博士
Issued Date: 2008-12-10
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: 罗振革
Keyword: 树突发育 ; 神经元活动 ; GGT ; Rho GTPases ; 脑源性神经营养因子 ; 原肌球蛋白相关激酶B
Alternative Title: TrkB-mediated Activation of Geranylgeranyltransferase I Promotes Dendritic Morphogenesis
Major: 神经生物学
Abstract: 神经元树突发育受到神经元活动和神经营养因子的调节,他们通过激活细胞内的信号蛋白如Rho GTPases 等来发挥作用。我们的研究表明,神经元活动和神经营养因子依赖的树突发育需要激活Geranylgeranyltransferase I (GGT) ——一种对Rho GTPases 进行脂化修饰的异戊二烯基转移酶。我们发现:1、过表达GGT 促进培养的海马神经元树突分枝增加,抑制或下调GGT的表达则产生相反的作用。2、高钾去极化和脑源性神经营养因子(brain-derived neurotrophic factor, BDNF) 能使培养的神经元GGT的活性增加。3、新奇复杂环境的刺激同样可以让小鼠海马GGT活性升高,表明在在体情况下,神经元活动增加也可以激活GGT。4、GGT与BDNF的受体原肌球蛋白相关激酶B (tropomyosin-related kinase B, TrkB) 有直接的相互作用,且这种相互作用可被高钾去极化所加强。5、破坏GGT-TrkB 的相互作用或抑制GGT的活性可以阻断高钾去极化与BDNF诱导的树突发育。6、过表达GGT底物Rac1不能被GGT修饰的突变体可以阻断GGT、高钾去极化与BDNF对树突发育的促进作用。综上所述,高钾去极化与BDNF诱导的树突发育可能是通过GGT介导的Rho GTPases 的异戊二烯化来完成的。
English Abstract: Dendrite morphogenesis is regulated by neuronal activity or neurotrophins, which may function by activating intrinsic signaling proteins, including Rho GTPases. Here we report that activity- and brain-derived neurotrophic factor (BDNF) - dependent dendritic morphogenesis requires activation of geranylgeranyltransferase I (GGT), a prenyltransferase which mediates lipid modification of Rho GTPases. Dendritic arborization in cultured hippocampal neurons was promoted by over-expression of GGT, and reduced by down-regulation of GGT. Furthermore, GGT was activated by neuronal depolarization or BDNF, both of which promote dendritic arborization, in cultured neurons. In addition, we found that GGT was activated in mice hippocampus after exploration of a novel enriched environment, suggesting that neural activity activates GGT in vivo. Interestingly, GGT was physically associated with tropomyosin-related kinase B (TrkB), the receptor for BDNF, and this association was enhanced by depolarization. Disrupting the GGT-TrkB interaction or down-regulating GGT activity attenuated depolarization- or BDNF-induced dendrite development. Finally, the effects of GGT, depolarization or BDNF on dendrite arborization were prevented by over-expressing Rac1 with the prenylation site deleted or mutated. Thus depolarization- or BDNF-dependent dendrite development may be mediated by GGT-induced prenylation of Rho GTPases.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2384
Appears in Collections:神经所(总)_学位论文

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Recommended Citation:
TrkB介导的蛋白异戊二烯基转移酶激活促进神经元树突发育.周秀萍[d].中国科学院上海生命科学研究院,2008.20-25
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