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Title: PKC-delta通过稳定Cdk5的激活因子p35调节皮层神经元的放射状迁移
Author: 赵春涛
Degree Level: 博士
Issued Date: 2009-12-04
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: 袁小兵
Keyword: 蛋白质稳定性 ; 大脑皮层 ; 放射状迁移 ; BDNF ; 磷酸化
Alternative Title: PKCδ Regulates Cortical Radial Migration by Stabilizing the Cdk5 Activator P35
Major: 神经生物学
Abstract: 细胞周期素依赖性激酶5(cyclin dependent kinase 5,Cdk5)及其激活因子p35对调节大脑皮层新生神经元的放射状迁移以及分层定位至关重要。然而,p35/Cdk5酶活性受细胞内外信号调节的机制仍不清楚。我们发现:新型PKC(novel PKC,nPKC)家族的一员-PKC在皮层神经元中有表达。PKC通过直接磷酸化的方式稳定野生型p35蛋白,而不能被PKC磷酸化的p35突变体则不受其保护。用胚胎子宫内电转特异的small interference RNA (siRNA, or RNAi)降低PKC的表达会严重地干扰皮层新生神经元的放射状迁移。这个迁移缺陷和降低p35的表达引起的缺陷非常相似,并且过表达野生型而不是突变的p35可以挽救细胞迁移。细胞外的促迁移信号分子-脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)能够激活PKC,而且BDNF对Cdk5的激活需要PKC的参与。PKC和p35对BDNF所促进的培养皮层神经元迁移都是必须的。因此,PKC可能通过维持细胞内合适的p35蛋白水平来调节大脑皮层神经元的放射状迁移。
English Abstract: Cyclin-dependent kinase 5 (Cdk5) and its activator p35 are critical for radial migration and lamination of cortical neurons. However, how this kinase is regulated by extracellular and intracellular signals during cortical morphogenesis remains unclear. Here we show that PKC, a member of novel PKC expressing in cortical neurons, could stabilize p35 by direct phosphorylation. PKC attenuated the degradation of p35 but not its mutant derivative which could not be phosphorylated by PKC Downregulation of PKC by in utero electroporation of specific small interference RNA (siRNA) severely impaired the radial migration of cortical neurons. This migration defect was similar to that caused by downregulation of p35 and could be prevented by co-transfection with the wild type but not mutant p35. Furthermore, PKC could be activated by the pro-migratory factor brain-derived neurotrophic factor (BDNF) and was required for the activation of Cdk5 by BDNF. Both PKCand p35 were required for the pro-migratory effect of BDNF on cultured newborn neurons. Both PKCand p35 were required for the pro-migratory effect of BDNF on cultured newborn neurons. Thus, PKC may promote cortical radial migration through maintaining the proper level of p35 in newborn neurons.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2412
Appears in Collections:神经所(总)_学位论文

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Recommended Citation:
PKC-delta通过稳定Cdk5的激活因子p35调节皮层神经元的放射状迁移.赵春涛[d].中国科学院上海生命科学研究院,2009.20-25
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