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Title: Neuregulin在调节神经前体细胞增殖以及少突胶质细胞分化过程中的相关机制
Author: 赖晨
Degree Level: 博士
Issued Date: 2004
Degree Grantor: 中国科学院中国科学神经科学研究所
Place of Degree Grantor: 中国科学神经科学研究所
Supervisor: 冯林音
Keyword: 神经前体细胞 ; 增殖 ; 磷脂酶C ; 蛋白激酶C ; 佛波酯 ; γ分泌酶 ; 核转运 ; 少突胶质细胞 ; 细胞的成熟 ; 髓鞘化
Alternative Title: Associated Mechanisms Involved in Neuregulin-lnduced Proliferation of Neural Progenitor Cells and Maturation of Oligodendrocytes
Abstract: 从大脑的海马区域可以分离出表达Nestin的神经前体细胞(neural progenitor cells, NPCs),这些细胞在即idermal growth factor(EGF)或basic fiboblast growth factor(bFGF)的作用下可以进行增殖。但是到目前为止,对调节神经前体细胞增殖的内在信号机制的了解还十分有限。我们的研究证明,象bFGF一样,Neuregulin娜(NRG)也可以有效地促进海马来源的神经前体细胞的增殖,并形成神经球(neurosphere),而且N邓还将神经前体细胞维持在前体的状态。用12-O-tetradecanoylphorbol-13-cotote(TpA)激活phospllol ipaseC(PLC)信号通路的下游效应器protein kinase C(PKC),可以模拟NRG引起的神经前体细胞的增殖。另外,TPA和NRG在促进神经球生长作用上的协同作用提示我们,NRG诱导的神经前体细胞的增殖作用可能是通过PLC/PKC信号传导通路来完成的。实验中我们还发现,NRG的一个重要的功能性受体ErbB4,与PLCy1蛋白有直接或间接的相互作用。抑制PLC信号通路的活性还将严重抑制神经前体细胞的增殖活动。我们的研究表明,PLC/PKC信号通路的活性在NRG诱导的海马来源的神经前体细胞的增殖作用中可能起着很重要的作用。越来越多的证据表明,受体ErbB4在其配体NRG的作用下将经过一系划蛋白质水解,其中包括Y分泌酶介导的蛋白质水解。ErbB4经过水解后将产生一个细胞内的片段EICD(the ErB4 intracellular domain)。已有文献报道这个片段会被转运到细胞核中并起着转录调节作用。虽然有研究表明\琳和ErbB4的相互作用可以促进少突胶质细胞的成熟,但是EICD和Y分泌酶在这个过程中的作用还不清楚。我们的研究证明,NRG和ErbB4的相互作用可以引起El娜在细胞核内的聚集,这种聚集与少突胶质细胞中髓鞘碱性蛋白MBP(myelin basic protein)的表达有一定的相关性。用ErbB4的抗体或了分泌酶的特异性抑制剂都可以阻断NRG对少突胶质细胞的成熟作用。另外,EICD在细胞核中的聚集对神经元或星状胶质细胞的成熟以及少突胶质细胞的早期发育没有明显的作用。在体外和体内实验中我们都发现,细胞发育得愈成熟,ErbB4的水解和向细胞核内转运的作用就愈强。在海马细胞发育成熟的过程中,这种表达趋势十分明显。我们的实验结果证明,γ分泌酶的活性和EICD的入核在NRG诱导的少突胶质细胞的成熟过程中起着很重要的作用,ErbB4在这个过程中以一种新的信号传递机制来调节少突胶质细胞的成熟。
English Abstract: Nestin-expressing neural progenitor cells (NPCs) have been isolated from hippocampus of brains and propagated with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). However, the underlying signaling mechanisms regulating NPC proliferation remain elusive. Here we showed that Neuregulin(31 (NRG), like bFGF, effectively promoted the proliferation of hippocampus-derived NPCs and maintained the progenitor states of NPCs. Activation of protein kinase C (PKC), a down-stream effector of phospholipase C (PLC), with 12-O-tetradecanoylphorboI- 13-acetate (TPA) mimicked the NRG-induced proliferation of NPCs. The synergic effect of TPA plus NRG on neurosphere growth further prompted us to find that NRG induced NPC propagation through PLC/PKC signaling pathway. ErbB4, an important functional receptor of NRG, had an interaction with PLCyi protein. In addition, inactivation of PLC pathway led to severe proliferative suppression of NPCs. Our study suggests that activation of PLC/PKC pathway may play an essential role in the NRG-induced proliferation of hippocampus-derived NPCs. Increasing evidences suggest that, after neuregulin (NRG) stimulation, ErbB4 undergoes a series of proteolysis, including y-secretase cleavage. The released ErB4 intracellular domain (EICD) is translocated into nucleus and has a transcriptional function. Although NRG-ErbB4 signaling mediates maturation of oligodendrocytes (OLs), the role of EICD and y-secretase in this process remain elusive. Here, we showed that NRG-ErbB4 interaction accumulated EICD in the nucleus and promoted the expression of myelin basic protein expression in OLs. Conversely, inhibitor of ErbB4 or y-secretase blocked the capacity of NRG. Nuclear accumulation of EICD did not influence maturation of neurons and astrocytes and early development of OLs. We also found that EICD translocation accorded a temporal pattern, consistent with the developmental gradient of hippocampus. Our data suggest that y-secretase activation and EICD nuclear translocation are required for OL maturation induced by NRG, and ErbB4 acts as a functional receptor depending on a new signaling cascade.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2251
Appears in Collections:神经所(总)_学位论文

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Recommended Citation:
Neuregulin在调节神经前体细胞增殖以及少突胶质细胞分化过程中的相关机制.赖晨[d].中国科学院中国科学神经科学研究所,2004.20-25
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