A Retained Intron in the 3'-UTR of Calm3 mRNA Mediates Its Staufen2- And Activity-Dependent Localization to Neuronal Dendrites

EMBO Rep. 2017 Oct;18(10):1762-1774. doi: 10.15252/embr.201744334. Epub 2017 Aug 1.

Abstract

Dendritic localization and hence local mRNA translation contributes to synaptic plasticity in neurons. Staufen2 (Stau2) is a well-known neuronal double-stranded RNA-binding protein (dsRBP) that has been implicated in dendritic mRNA localization. The specificity of Stau2 binding to its target mRNAs remains elusive. Using individual-nucleotide resolution CLIP (iCLIP), we identified significantly enriched Stau2 binding to the 3'-UTRs of 356 transcripts. In 28 (7.9%) of those, binding occurred to a retained intron in their 3'-UTR The strongest bound 3'-UTR intron was present in the longest isoform of Calmodulin 3 (Calm3L ) mRNA Calm3L 3'-UTR contains six Stau2 crosslink clusters, four of which are in this retained 3'-UTR intron. The Calm3L mRNA localized to neuronal dendrites, while lack of the 3'-UTR intron impaired its dendritic localization. Importantly, Stau2 mediates this dendritic localization via the 3'-UTR intron, without affecting its stability. Also, NMDA-mediated synaptic activity specifically promoted the dendritic mRNA localization of the Calm3L isoform, while inhibition of synaptic activity reduced it substantially. Together, our results identify the retained intron as a critical element in recruiting Stau2, which then allows for the localization of Calm3L mRNA to distal dendrites.

Keywords: Calm3; Stau2; intron; neuronal activity; neuronal mRNA regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions*
  • Animals
  • Calmodulin / genetics*
  • Dendrites / metabolism*
  • HeLa Cells
  • Hippocampus / cytology
  • Humans
  • Introns*
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism*
  • RNA, Double-Stranded / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Rats

Substances

  • 3' Untranslated Regions
  • Calmodulin
  • Nerve Tissue Proteins
  • RNA, Double-Stranded
  • RNA, Messenger
  • RNA-Binding Proteins
  • Stau2 protein, rat
  • stau2 protein, mouse