复杂多样的形态是神经元的重要特征。在发育过程中，神经元产生许多突起，伸展出的树突结构接受并整合传入信息，与学习记忆等高级脑功能密切相关。虽然在大脑发育过程或接受外界活性刺激的情况下，神经元的形态会发生精细的重构，但这些复杂有序的树突结构是如何形成，及其在脑损伤或外界活性刺激条件下结构重塑的机制尚不清楚。外界的信号刺激以及细胞内的基因转录对树突的结构均有重要的作用。CREB（环腺苷酸应答元件结合蛋白）作为一个经典的核内转录因子，可以响应外界的信号，启动下游基因的转录，最终调节树突的形态发育；然而对于CREB如何作为一个介导因子发挥其调控作用、外界的刺激如何诱导CREB下游基因的转录从而影响树突的发育结构的机制却并不清楚。
2009年2月25日《神经科学杂志》（Journal of Neuroscience）发表了中国科学院上海生命科学研究院神经科学研究所熊志奇研究组关于神经元电活性如何决定神经元形态的工作《CREB共激活因子TORC1调控活性依赖的CREB下游基因转录和皮层神经元的树突发育》，主要由博士生李帅完成。发现神经元电活性可以诱导CREB的转录共激活因子TORC1从胞浆穿梭到胞核，从而启动CREB下游基因的转录；而盐诱导激酶SIK，CREB的一个下游基因，则通过负反馈机制磷酸化TORC1并将其从核内排除，从而终止了CREB下游基因的转录。此项研究的意义在于为CREB介导的基因转录提供了新的机理，并且解释了CREB激活和下游基因表达在时程上的不一致性。研究还进一步发现TORC1对树突的发育有着重要的作用；通过体内和体外基因操作发现干扰TORC1可以抑制神经元电活性诱导的树突发育，而过表达TORC1则会明显促进树突的复杂程度。在神经系统中，CREB具有重要而广泛的功能，并且在学习记忆中起着至关重要的功能。这项工作发现TORC1/SIK1是调控神经元中CREB下游基因转录的钥匙，对神经元树突发育起重要的调控功能。
该项工作得到了国家科技部、国家自然科学基金委和中国科学院资助。（生物谷Bioon.com）
生物谷推荐原始出处：
J. Neurosci., Feb 2009; 29: 2334 - 2343 ; doi:10.1523/JNEUROSCI.2296-08.2009
TORC1 Regulates Activity-Dependent CREB-Target Gene Transcription and Dendritic Growth of Developing Cortical Neurons
Shuai Li,1 Chi Zhang,1 Hiroshi Takemori,2 Yang Zhou,1 and Zhi-Qi Xiong1
1Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and 2Laboratory of Cell Signal and Metabolism, National Institute of Biomedical Innovation, Saito, Ibaraki, Osaka 567-0085, Japan
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 cAMP response element-binding protein (CREB)-mediated gene transcription during dendritic development are not well understood. Herein we report that the CREB coactivator 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 downregulating TORC1 inhibited activity-dependent dendritic growth in vitro and in vivo. Together, these results suggest that neuronal activity-dependent dendritic growth in developing cortical neurons relies on transient TORC1-mediated CREB-target gene transcription.
