Abstract:
: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, suggesting shRNA-mediated off-target toxicity. This effect was not 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.
journal_name
Neuronjournal_title
Neuronauthors
Baek ST,Kerjan G,Bielas SL,Lee JE,Fenstermaker AG,Novarino G,Gleeson JGdoi
10.1016/j.neuron.2014.04.036subject
Has Abstractpub_date
2014-06-18 00:00:00pages
1255-1262issue
6eissn
0896-6273issn
1097-4199journal_volume
82pub_type
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