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首页> 外文期刊>Neuron >Off-target effect of doublecortin family shRNA on neuronal migration associated with endogenous MicroRNA dysregulation
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Off-target effect of doublecortin family shRNA on neuronal migration associated with endogenous MicroRNA dysregulation

机译：双皮质素家族shRNA对与内源性MicroRNA失调相关的神经元迁移的脱靶作用

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摘要

Acute gene inactivation using short hairpin RNA (shRNA, knockdown) in developing brain is a powerful technique to study genetic function; however, discrepancies between knockdown and knockout murine phenotypes have left unanswered questions. For example, doublecortin (Dcx) knockdown but not knockout shows a neocortical neuronal migration phenotype. Here we report that in utero electroporation of shRNA, but not siRNA or miRNA, to Dcx demonstrates a migration phenotype in Dcx knockouts akin to the effect in wild-type mice, suggestingshRNA-mediated off-target toxicity. This effect wasnot limited to Dcx, as it was observed in Dclk1 knockouts, as well as with a fraction of scrambled shRNAs, suggesting a sequence-dependent but not sequence-specific effect. Profiling RNAs from electroporated cells showed a defect in endogenous let7 miRNA levels, and disruption of let7 or Dicer recapitulated the migration defect. The results suggest that shRNA-mediated knockdown can produce untoward migration effects by altering endogenous miRNA pathways.
机译：在发育中的大脑中使用短发夹RNA（shRNA，敲低）进行急性基因失活是研究遗传功能的强大技术。但是，敲除和敲除小鼠表型之间的差异留下了未解决的问题。例如，双皮质素（Dcx）敲除但未敲除显示出新皮层神经元迁移表型。在这里，我们报告说，在子宫内将shRNA而不是siRNA或miRNA电穿孔到Dcx，证明Dcx敲除物中的迁移表型类似于野生型小鼠的作用，表明shRNA介导的脱靶毒性。此作用不限于Dcx，如在Dclk1基因敲除中观察到的那样，以及一部分加扰的shRNA的存在，表明了序列依赖性但非序列特异性的作用。从电穿孔细胞中分析出的RNA显示出内源性let7 miRNA水平存在缺陷，而let7或Dicer的破坏概括了迁移缺陷。结果表明，shRNA介导的敲低可以通过改变内源性miRNA途径产生不利的迁移作用。

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