FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences

Elife. 2020 Jun 8;9:e52621. doi: 10.7554/eLife.52621.

Abstract

The sorting of RNA molecules to subcellular locations facilitates the activity of spatially restricted processes. We have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these transcripts contain an enrichment of G-quadruplex sequences in their 3' UTRs, suggesting that FMRP recognizes them to promote RNA localization. We observed similar results in neurons derived from Fragile X Syndrome patients. We identified the RGG domain of FMRP as important for binding G-quadruplexes and the transport of G-quadruplex-containing transcripts. Finally, we found that the translation and localization targets of FMRP were distinct and that an FMRP mutant that is unable to bind ribosomes still promoted localization of G-quadruplex-containing messages. This suggests that these two regulatory modes of FMRP may be functionally separated. These results provide a framework for the elucidation of similar mechanisms governed by other RNA-binding proteins.

Keywords: FMRP; RNA localization; chromosomes; fragile x syndrome; gene expression; genetics; genomics; human; mouse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Fragile X Mental Retardation Protein* / chemistry
  • Fragile X Mental Retardation Protein* / genetics
  • Fragile X Mental Retardation Protein* / metabolism
  • Fragile X Syndrome
  • G-Quadruplexes
  • Gene Knockout Techniques
  • Mice
  • Neurites / metabolism*
  • Neurons / metabolism*
  • RNA Transport / genetics*
  • RNA, Messenger* / chemistry
  • RNA, Messenger* / genetics
  • RNA, Messenger* / metabolism

Substances

  • Fmr1 protein, mouse
  • RNA, Messenger
  • Fragile X Mental Retardation Protein

Associated data

  • GEO/GSE137878
  • GEO/GSE67828
  • GEO/GSE116342
  • GEO/GSE51572