A large-scale functional screen identifies Nova1 and Ncoa3 as regulators of neuronal miRNA function

EMBO J. 2015 Sep 2;34(17):2237-54. doi: 10.15252/embj.201490643. Epub 2015 Jun 23.

Abstract

MicroRNAs (miRNAs) are important regulators of neuronal development, network connectivity, and synaptic plasticity. While many neuronal miRNAs were previously shown to modulate neuronal morphogenesis, little is known regarding the regulation of miRNA function. In a large-scale functional screen, we identified two novel regulators of neuronal miRNA function, Nova1 and Ncoa3. Both proteins are expressed in the nucleus and the cytoplasm of developing hippocampal neurons. We found that Nova1 and Ncoa3 stimulate miRNA function by different mechanisms that converge on Argonaute (Ago) proteins, core components of the miRNA-induced silencing complex (miRISC). While Nova1 physically interacts with Ago proteins, Ncoa3 selectively promotes the expression of Ago2 at the transcriptional level. We further show that Ncoa3 regulates dendritic complexity and dendritic spine maturation of hippocampal neurons in a miRNA-dependent fashion. Importantly, both the loss of miRNA activity and increased dendrite complexity upon Ncoa3 knockdown were rescued by Ago2 overexpression. Together, we uncovered two novel factors that control neuronal miRISC function at the level of Ago proteins, with possible implications for the regulation of synapse development and plasticity.

Keywords: Ago2; Ncoa3; Nova1; dendrite; miRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Argonaute Proteins / biosynthesis*
  • Argonaute Proteins / genetics
  • Gene Expression Regulation / physiology*
  • HEK293 Cells
  • Humans
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Neurons / cytology
  • Neurons / metabolism*
  • Nuclear Receptor Coactivator 3 / genetics
  • Nuclear Receptor Coactivator 3 / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Ago2 protein, rat
  • Argonaute Proteins
  • MicroRNAs
  • Nova1 protein, rat
  • RNA-Binding Proteins
  • Nuclear Receptor Coactivator 3