近日,，國際著名雜志Journal of Cell Science在線刊登了上海生科院健康所研究人員的最新研究成果“miR-132 regulates the differentiation of dopamine neurons by directly targeting Nurr1 expression，”文章中,，研究者發(fā)現(xiàn)了miroRNA調(diào)節(jié)多巴胺能神經(jīng)元分化的新機(jī)制,。
眾所周知，中腦多巴胺能神經(jīng)元的退行性死亡是帕金森病的最顯著特征,，了解其發(fā)育的分子生物學(xué)機(jī)制對(duì)探索帕金森病的發(fā)病機(jī)理以及治療帕金森病都有著至關(guān)重要,。然而,，對(duì)于胚胎干細(xì)胞向多巴胺能神經(jīng)元的發(fā)育過程的機(jī)制至今還不清楚。
健康所神經(jīng)基因組博士研究生楊德華等在樂衛(wèi)東研究員的指導(dǎo)下通過對(duì)于胚胎干細(xì)胞向多巴胺能神經(jīng)元的發(fā)育過程中microRNA表達(dá)譜的變化分析發(fā)現(xiàn)了一些新的microRNA,， 并且鑒定了其中一個(gè)miR-132在多巴胺能神經(jīng)元發(fā)育的過程中表達(dá)顯著變化. 進(jìn)一步研究表明miR-132能通過直接靶向Nurr1從而調(diào)節(jié)胚胎干細(xì)胞向多巴胺能神經(jīng)元的分化,。該研究在國際上首次詳細(xì)闡述了miR-132作為胚胎干細(xì)胞向多巴胺能神經(jīng)元的調(diào)節(jié)作用和分子機(jī)制，對(duì)于帕金森病的發(fā)病機(jī)制的了解和未來以胚胎干細(xì)胞分化為多巴胺能神經(jīng)元的細(xì)胞治療帕金森疾病提供了重要理論依據(jù)和應(yīng)用價(jià)值,。
樂衛(wèi)東教授長期以來一直在探索轉(zhuǎn)錄因子Nurr1的功能機(jī)制,， 他領(lǐng)導(dǎo)的研究組第一次發(fā)現(xiàn)了 Nurr1是多巴胺能神經(jīng)元的最重要的調(diào)控因子。同時(shí)博士研究生衡鑫在樂教授指導(dǎo)下,， 得到最新的研究成果表明,，Nurr1通過轉(zhuǎn)錄調(diào)節(jié)軸突導(dǎo)向基因TopIIβ影響了多巴胺能神經(jīng)元的軸突生長，研究結(jié)果發(fā)表在本期的Molecular Neurodegeneration上,。
該工作得到了國家自然科學(xué)基金委及科技部973項(xiàng)目的經(jīng)費(fèi)支持,。（生物谷Bioon.com）
doi:10.1242/jcs.086421
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miR-132 regulates the differentiation of dopamine neurons by directly targeting Nurr1 expression
Dehua Yang*, Ting Li*, Yi Wang, Yuanjia Tang, Huijuan Cui, Yu Tang, Xiaojie Zhang, Degui Chen, Nan Shen and Weidong Le‡
Although it is well established that embryonic stem (ES) cells have the potential to differentiate into dopamine neurons, the molecular basis of this process, particularly the role of microRNAs (miRNAs), remains largely unknown. Here we report that miR-132 plays a key role in the differentiation of dopamine neurons by directly regulating the expression of Nurr1. First, we constructed a mouse ES cell line CGR8, which stably expresses GFP under the tyrosine hydroxylase (TH)-promoter, so the TH-positive neurons could be easily sorted out by a fluorescence-activated cell sorter (FACS). Then, we performed a miRNA array analysis in the purified TH-positive neurons and found that 45 of 585 miRNAs have expression level change >5 fold during dopamine neuron differentiation. Among the 45 miRNAs, we were particularly interested in miR-132 because this miRNA has been reported as being highly expressed in neurons and having a potential role in neurodegenerative diseases. We found that the direct down-regulation of endogenous miR-132 induced by miR-132 antisense oligonucleotide (miR-132-ASO) promoted the differentiation of TH-positive neurons, while ectopic expression of miR-132 in ES cells reduced the number of differentiated TH-positive neurons but did not change the total number of differentiated neurons. Furthermore, we documented that miR-132-ASO could significantly reverse the miR-132-mediated suppression of TH-positive neuron differentiation. Moreover, through bioinformatics assay we identified Nurr1 gene as a potential molecular target of miR-132. Using luciferase-reporter assay and Western blot analysis, we demonstrated that miR-132 could directly regulate the expression of Nurr1. Collectively, our data provide the first evidence that miR-132 is an important molecule regulating ES cell differentiation into dopamine neurons by directly targeting Nurr1 expression.
