1月15日，国际期刊《生物化学杂志》(JBC) 在线发表了中科院上海生科院生化与细胞所景乃禾研究组及程乐平研究组在Nestin基因表达调控研究的一项新发现。
动物体早期发育过程中，中枢神经系统发育是一个重要事件。Nestin是一种中等纤维蛋白，它在哺乳动物神经前体细胞中高表达，已被广泛用作神经前体细胞的标志分子。研究Nestin基因的表达调控规律，将有助于人们认识神经前体细胞的生物特性。Nestin基因的第二内含子具有中枢神经系统（Central nervous system, CNS）组织特异性增强子活性，然而调控该基因在神经发育过程中表达的转录因子尚不明确。在这项工作中，金志刚等研究人员首先发现小鼠Nestin 基因的第二个内含子能指导报告基因LacZ在发育的神经系统中专一表达。鸡胚电转和转基因小鼠实验进一步证实，小鼠Nestin基因的第二内含子核心序列能指导报告基因在胚胎发育中的CNS特异表达。利用视黄酸（Retinoic acid, RA）诱导的P19细胞体外神经分化模型，研究者发现小鼠Nestin基因在神经分化过程中瞬时上调，这一表达变化受到第二内含子中组织特异性增强子的调控。该增强子的活性在未诱导的P19EC细胞中主要依赖于Sox、POU、HRE和SF1位点，而在P19神经前体细胞中主要依赖于Sox、POU和HRE位点。进一步实验表明，转录因子Sox2及SF1介导Nestin基因在未分化的P19细胞中表达，而转录因子Sox2、Brn1及Brn2决定Nestin基因在P19神经前体细胞中表达。有趣的是，研究者发现在小鼠胚胎及P19细胞神经分化的不同时期，POU家族的不同成员通过POU因子结合位点调控了Nestin基因的表达，即在胚胎epiblast及未诱导的P19EC细胞中，Oct1 和Oct4 结合于POU位点，而在胚胎及P19神经前体细胞中，Brn1和Brn2与该位点结合。
这些工作提出了不同转录因子的时空组合决定Nestin基因表达的新机制，这必将丰富人们对神经前体细胞的生物特性的认识。（生物谷Bioon.com）
生物谷推荐原始出处：
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.
