Evidence for evolutionary divergence of activity-dependent gene expression in developing neurons
Evidence for evolutionary divergence of activity-dependent gene expression in developing neurons
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DOI：
10.7554/elife.20337
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发表时间：
2016-10-01
期刊：
影响因子：
7.7
通讯作者：
Hardingham, Giles E.
中科院分区：
文献类型：
--
作者：
Qiu, Jing;McQueen, Jamie;Hardingham, Giles E.
人类和低等哺乳动物实验系统之间基因调控的进化差异尚不完全清楚，这是一个潜在的翻译障碍，在初级组织可用性差的神经元中很难克服。基于啮齿动物的研究表明，活动依赖的转录程序介导了神经元发育中的无数功能，但它们在人类神经元中的保护程度尚不清楚。我们比较了人类干细胞来源的皮质神经元发育中活性依赖的转录反应与原代或干细胞来源的小鼠皮质神经元发育中诱导的转录反应。虽然活性依赖的基因反应性与发育阶段或起源（原代组织与干细胞）的关系不大，但观察到明显的物种依赖差异。此外，在携带人类21号染色体的非整倍体小鼠神经元中重现了不同物种特异性基因同源调控，暗示启动子/增强子序列差异是一个因素，包括人类特异性活性响应的AP-1位点。这些发现支持使用人类神经元系统来探测生理刺激或药物制剂的转录反应。
Evolutionary differences in gene regulation between humans and lower mammalian experimental systems are incompletely understood, a potential translational obstacle that is challenging to surmount in neurons, where primary tissue availability is poor. Rodent-based studies show that activity-dependent transcriptional programs mediate myriad functions in neuronal development, but the extent of their conservation in human neurons is unknown. We compared activity-dependent transcriptional responses in developing human stem cell-derived cortical neurons with those induced in developing primary-or stem cell-derived mouse cortical neurons. While activity-dependent gene-responsiveness showed little dependence on developmental stage or origin (primary tissue vs. stem cell), notable species-dependent differences were observed. Moreover, differential species-specific gene ortholog regulation was recapitulated in aneuploid mouse neurons carrying human chromosome-21, implicating promoter/enhancer sequence divergence as a factor, including human-specific activity-responsive AP-1 sites. These findings support the use of human neuronal systems for probing transcriptional responses to physiological stimuli or indeed pharmaceutical agents.