Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition
Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition
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DOI：
10.1038/nature03663
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发表时间：
2005-06-16
期刊：
影响因子：
64.8
通讯作者：
Gage, FH
中科院分区：
文献类型：
--
作者：
Muotri, AR;Chu, VT;Gage, FH
揭示神经元体细胞多样化的机制仍然是理解大脑组织和功能的个体差异的核心挑战。在这里，我们证明了工程化的人类LINE-1(即长时间散布的核素-1；也称为L1)元件可以在大鼠海马神经干细胞来源的神经元前体中逆转录转座。由此产生的逆转座事件可以改变神经元基因的表达，这反过来又可以影响体外培养的神经细胞的命运。我们进一步证明，在转基因小鼠中逆转录转位人L1会导致神经元体细胞嵌合体。这种作用的分子机制可能是通过Sox2介导的，因为在神经元分化的早期阶段，Sox2表达的减少与L1转录和逆转录转座的增加有关。因此，我们的数据表明，神经元基因组可能不是静止的，但一些可能是镶嵌的，因为从头开始的L1逆转座子事件。
Revealing the mechanisms for neuronal somatic diversification remains a central challenge for understanding individual differences in brain organization and function. Here we show that an engineered human LINE-1 (for long interspersed nuclear element-1; also known as L1) element can retrotranspose in neuronal precursors derived from rat hippocampus neural stem cells. The resulting retrotransposition events can alter the expression of neuronal genes, which, in turn, can influence neuronal cell fate in vitro. We further show that retrotransposition of a human L1 in transgenic mice results in neuronal somatic mosaicism. The molecular mechanism of action is probably mediated through Sox2, because a decrease in Sox2 expression during the early stages of neuronal differentiation is correlated with increases in both L1 transcription and retrotransposition. Our data therefore indicate that neuronal genomes might not be static, but some might be mosaic because of de novo L1 retrotransposition events.