The RNA-binding protein ARPP21 controls dendritic branching by functionally opposing the miRNA it hosts

Nat Commun. 2018 Mar 26;9(1):1235. doi: 10.1038/s41467-018-03681-3.


About half of mammalian miRNA genes lie within introns of protein-coding genes, yet little is known about functional interactions between miRNAs and their host genes. The intronic miRNA miR-128 regulates neuronal excitability and dendritic morphology of principal neurons during mouse cerebral cortex development. Its conserved host genes, R3hdm1 and Arpp21, are predicted RNA-binding proteins. Here we use iCLIP to characterize ARPP21 recognition of uridine-rich sequences with high specificity for 3'UTRs. ARPP21 antagonizes miR-128 activity by co-regulating a subset of miR-128 target mRNAs enriched for neurodevelopmental functions. Protein-protein interaction data and functional assays suggest that ARPP21 acts as a positive post-transcriptional regulator by interacting with the translation initiation complex eIF4F. This molecular antagonism is reflected in inverse activities during dendritogenesis: miR-128 overexpression or knockdown of ARPP21 reduces dendritic complexity; ectopic ARPP21 leads to an increase. Thus, we describe a unique example of convergent function by two products of a single gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Cytoplasmic Granules / metabolism
  • Dendrites / physiology*
  • Eukaryotic Initiation Factor-4F / metabolism
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice
  • MicroRNAs / genetics*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphoproteins / physiology*
  • Protein Interaction Maps
  • Proteolysis
  • RNA Processing, Post-Transcriptional
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / physiology*


  • 3' Untranslated Regions
  • Eukaryotic Initiation Factor-4F
  • MicroRNAs
  • Mirn128 microRNA, mouse
  • Phosphoproteins
  • RNA-Binding Proteins
  • cyclic AMP-regulated phosphoprotein ARPP-21