1月15日,，國(guó)際期刊《生物化學(xué)雜志》(JBC) 在線發(fā)表了中科院上海生科院生化與細(xì)胞所景乃禾研究組及程樂平研究組在Nestin基因表達(dá)調(diào)控研究的一項(xiàng)新發(fā)現(xiàn)。
動(dòng)物體早期發(fā)育過程中,，中樞神經(jīng)系統(tǒng)發(fā)育是一個(gè)重要事件,。Nestin是一種中等纖維蛋白，它在哺乳動(dòng)物神經(jīng)前體細(xì)胞中高表達(dá),，已被廣泛用作神經(jīng)前體細(xì)胞的標(biāo)志分子,。研究Nestin基因的表達(dá)調(diào)控規(guī)律，將有助于人們認(rèn)識(shí)神經(jīng)前體細(xì)胞的生物特性,。Nestin基因的第二內(nèi)含子具有中樞神經(jīng)系統(tǒng)（Central nervous system, CNS）組織特異性增強(qiáng)子活性,，然而調(diào)控該基因在神經(jīng)發(fā)育過程中表達(dá)的轉(zhuǎn)錄因子尚不明確。在這項(xiàng)工作中,，金志剛等研究人員首先發(fā)現(xiàn)小鼠Nestin 基因的第二個(gè)內(nèi)含子能指導(dǎo)報(bào)告基因LacZ在發(fā)育的神經(jīng)系統(tǒng)中專一表達(dá),。雞胚電轉(zhuǎn)和轉(zhuǎn)基因小鼠實(shí)驗(yàn)進(jìn)一步證實(shí)，小鼠Nestin基因的第二內(nèi)含子核心序列能指導(dǎo)報(bào)告基因在胚胎發(fā)育中的CNS特異表達(dá),。利用視黃酸（Retinoic acid, RA）誘導(dǎo)的P19細(xì)胞體外神經(jīng)分化模型,，研究者發(fā)現(xiàn)小鼠Nestin基因在神經(jīng)分化過程中瞬時(shí)上調(diào)，這一表達(dá)變化受到第二內(nèi)含子中組織特異性增強(qiáng)子的調(diào)控,。該增強(qiáng)子的活性在未誘導(dǎo)的P19EC細(xì)胞中主要依賴于Sox,、POU、HRE和SF1位點(diǎn),，而在P19神經(jīng)前體細(xì)胞中主要依賴于Sox,、POU和HRE位點(diǎn),。進(jìn)一步實(shí)驗(yàn)表明，轉(zhuǎn)錄因子Sox2及SF1介導(dǎo)Nestin基因在未分化的P19細(xì)胞中表達(dá),，而轉(zhuǎn)錄因子Sox2,、Brn1及Brn2決定Nestin基因在P19神經(jīng)前體細(xì)胞中表達(dá)。有趣的是,，研究者發(fā)現(xiàn)在小鼠胚胎及P19細(xì)胞神經(jīng)分化的不同時(shí)期,，POU家族的不同成員通過POU因子結(jié)合位點(diǎn)調(diào)控了Nestin基因的表達(dá)，即在胚胎epiblast及未誘導(dǎo)的P19EC細(xì)胞中,，Oct1 和Oct4 結(jié)合于POU位點(diǎn),，而在胚胎及P19神經(jīng)前體細(xì)胞中，Brn1和Brn2與該位點(diǎn)結(jié)合,。
這些工作提出了不同轉(zhuǎn)錄因子的時(shí)空組合決定Nestin基因表達(dá)的新機(jī)制,，這必將豐富人們對(duì)神經(jīng)前體細(xì)胞的生物特性的認(rèn)識(shí)。（生物谷Bioon.com）
生物谷推薦原始出處：
J. Biol. Chem, 10.1074/jbc.M805632200
Different transcription factors regulate nestin gene expression during P19 cell neural differentiation and central nervous system development
Zhigang Jin, Li Liu, Wei Bian, Yongfeng Chen, Guoliang Xu, Leping Cheng, and Naihe Jing
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai
Nestin is a molecular marker for neural progenitor cells. Rat and human nestin genes possess a central nervous system-specific enhancer within their second introns. However, the transcription factors that bind to the nestin enhancer have not been fully elucidated. Here, we show that the second intron of the mouse nestin gene is sufficient to drive reporter gene expression in the developing nervous system. The core sequence of this central nervous system-specific enhancer localizes to the 3' 320-bp region. Cis-elements for Sox and POU family transcription factors and hormone responsive element (HRE) are essential for nestin expression during embryonic carcinoma (EC) P19 cell neural differentiation and in the developing chick neural tube. Interestingly, different transcription factors bind to the nestin enhancer at different stages of P19 cell neural differentiation and central nervous system development. Sox2 and SF1 may mediate basal nestin expression in undifferentiated P19EC cells, while Sox2, Brn1 and Brn2 bind to the enhancer in P19 neural progenitor cells (NPCs). Similarly, in vivo, Oct1 binds to the nestin enhancer in embryonic day 8.5 (E8.5) mouse embryos, and Oct1, Brn1 and Brn2 bind to this enhancer in E10.5 and E12.5 mouse embryos. Our studies therefore suggest a temporal coordination of transcription factors in determining nestin gene expression.
