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Title: 神经元活性诱导的CREB目标基因转录和皮层神经元树突发育
Author: 李帅
Degree Level: 博士
Issued Date: 2009-04-10
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: 熊志奇
Keyword: 神经元 ; 树突生长 ; 神经元电活性 ; CREB ; TORC1
Alternative Title: TORC1 Regulates Activity-dependent CREB-target Gene Transcription and Dendritic Growth of Developing Cortical Neurons
Major: 神经生物学
Abstract: cAMP 反应元件结合蛋白(cAMP response element binding protein,CREB)及其家族是一类研究非常广泛的转录因子,其介导的基因转录具有非常重要的功能,其中包括神经元树突的生长。然而,在树突发育中,CREB如何介导基因的转录的机制并不是很清楚。通过我们的研究,我们发现CREB的共激活分子TORC1(Transducers of regulated CREB)在CREB介导的基因转录以发育过程中树突的生长中具有重要的功能。通过电压门控通道,钙离子大量内流激活钙调神经磷酸酶(Calcineurin),从而介导TORC1的去磷酸化,最终TORC1穿过核膜进入核中。TORC1在细胞核里聚集然后开启CREB目标基因的转录,其中包括盐诱导激酶SIK1(salt-inducible kinase 1)。在持续的去极化过程中,合成的SIK1磷酸化TORC1从而最终导致TORC1出核,在这个过程中,TORC1诱导的SIK1表达又反馈过来抑制CREB的基因转录。过表达TORC1 可以促进本底和神经元活性状态下的树突发育,然而表达突变型TORC1(dn-TORC1)或者敲除TORC1可以抑制神经元电活性诱导的树突发育。总之,我们的研究表示神经元活性诱导的树突发育依赖于TORC1介导的CREB目标基因的转录。
English Abstract: CREB-target gene transcription during neuronal excitation is important for many aspects of neuronal development and function, including dendrite morphogenesis. However, the signaling events that regulate CREB-mediated gene transcription during dendritic development are not well understood. Herein we report that the CREB co-activator TORC1 (transducer of regulated CREB 1) is required for activity-dependent CREB-target gene expression and dendrite growth in developing cortical neurons. Ca2+ influx via voltage-gated calcium channels induced TORC1 dephosphorylation and translocation into the nucleus in a calcineurin-dependent manner. Nuclear accumulation of TORC1 initiated the expression of CREB-target genes, including Salt-Inducible Kinase 1 (SIK1). In response of persistent depolarization, de novo SIK1 protein in turn promoted TORC1 phosphorylation and consequent depletion of nucleus-localized TORC1. SIK1 induction thus appears to act as a negative feedback signal that prevents persistent CREB/TORC1-dependent transcription in the face of long-lasting neuronal activity. Overexpressing wild type TORC1 promoted basal as well as activity-induced dendritic growth, whereas expressing a dominant-negative form of TORC1 or down-regulating TORC1 inhibited activity-dependent dendritic growth in vitro and in vivo. Taken together, these results suggest that neuronal activity-dependent dendritic growth in developing cortical neurons relies on transient TORC1-mediated CREB-target gene transcription.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2355
Appears in Collections:神经所(总)_学位论文

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Recommended Citation:
神经元活性诱导的CREB目标基因转录和皮层神经元树突发育.李帅[d].中国科学院上海生命科学研究院,2009.20-25
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