復(fù)雜多樣的形態(tài)是神經(jīng)元的重要特征。在發(fā)育過程中,，神經(jīng)元產(chǎn)生許多突起，伸展出的樹突結(jié)構(gòu)接受并整合傳入信息,，與學(xué)習(xí)記憶等高級腦功能密切相關(guān),。雖然在大腦發(fā)育過程或接受外界活性刺激的情況下，神經(jīng)元的形態(tài)會發(fā)生精細(xì)的重構(gòu),，但這些復(fù)雜有序的樹突結(jié)構(gòu)是如何形成,，及其在腦損傷或外界活性刺激條件下結(jié)構(gòu)重塑的機制尚不清楚。外界的信號刺激以及細(xì)胞內(nèi)的基因轉(zhuǎn)錄對樹突的結(jié)構(gòu)均有重要的作用,。CREB（環(huán)腺苷酸應(yīng)答元件結(jié)合蛋白）作為一個經(jīng)典的核內(nèi)轉(zhuǎn)錄因子,，可以響應(yīng)外界的信號，啟動下游基因的轉(zhuǎn)錄,，最終調(diào)節(jié)樹突的形態(tài)發(fā)育,；然而對于CREB如何作為一個介導(dǎo)因子發(fā)揮其調(diào)控作用、外界的刺激如何誘導(dǎo)CREB下游基因的轉(zhuǎn)錄從而影響樹突的發(fā)育結(jié)構(gòu)的機制卻并不清楚,。
2009年2月25日《神經(jīng)科學(xué)雜志》（Journal of Neuroscience）發(fā)表了中國科學(xué)院上海生命科學(xué)研究院神經(jīng)科學(xué)研究所熊志奇研究組關(guān)于神經(jīng)元電活性如何決定神經(jīng)元形態(tài)的工作《CREB共激活因子TORC1調(diào)控活性依賴的CREB下游基因轉(zhuǎn)錄和皮層神經(jīng)元的樹突發(fā)育》,，主要由博士生李帥完成。發(fā)現(xiàn)神經(jīng)元電活性可以誘導(dǎo)CREB的轉(zhuǎn)錄共激活因子TORC1從胞漿穿梭到胞核,，從而啟動CREB下游基因的轉(zhuǎn)錄,；而鹽誘導(dǎo)激酶SIK，CREB的一個下游基因,，則通過負(fù)反饋機制磷酸化TORC1并將其從核內(nèi)排除,，從而終止了CREB下游基因的轉(zhuǎn)錄。此項研究的意義在于為CREB介導(dǎo)的基因轉(zhuǎn)錄提供了新的機理,，并且解釋了CREB激活和下游基因表達(dá)在時程上的不一致性,。研究還進(jìn)一步發(fā)現(xiàn)TORC1對樹突的發(fā)育有著重要的作用；通過體內(nèi)和體外基因操作發(fā)現(xiàn)干擾TORC1可以抑制神經(jīng)元電活性誘導(dǎo)的樹突發(fā)育，而過表達(dá)TORC1則會明顯促進(jìn)樹突的復(fù)雜程度,。在神經(jīng)系統(tǒng)中,，CREB具有重要而廣泛的功能，并且在學(xué)習(xí)記憶中起著至關(guān)重要的功能,。這項工作發(fā)現(xiàn)TORC1/SIK1是調(diào)控神經(jīng)元中CREB下游基因轉(zhuǎn)錄的鑰匙,，對神經(jīng)元樹突發(fā)育起重要的調(diào)控功能。
該項工作得到了國家科技部,、國家自然科學(xué)基金委和中國科學(xué)院資助,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
