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

• Type of Material: Article
• Authors: Raeann Goering, University of Colorado; Laura Hudish, University of Colorado; Bryan B. Guzman, University of North Carolina; Nisha Raj, Emory University; Gary Bassell, Emory University; Holger A. Russ, University of Colorado; Daniel Dominguez, University of North Carolina; J. Matthew Taliaferro, University of Colorado
• Language: English
• Date: 2020-06-08
• Publisher: eLife Sciences Publications Ltd.
• Publication Version: Final Published Version
• Copyright Statement: © Goering et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.7554/eLife.52621
• Title of Journal or Parent Work: eLife
• Volume: 9
• Start Page: 1
• End Page: 31
• Grant/Funding Information: University of Colorado RNA Bioscience Initiative to J Matthew Taliaferro.; Culshaw Junior Investigator Award to Holger A Russ.; Juvenile Diabetes Research Foundation to Holger A Russ.; This work was funded by the RNA Bioscience Initiative at the University of Colorado Anschutz Medical Campus (JMT), a Webb-Waring Early Career Investigator Award from the Boettcher Foundation (AWD-182937) (JMT), NIH1R35GM133885 (JMT), NIHDK120444 (HAR), NIHAI140044 (HAR), NIHDK118803-01A1 (LIH) NIH1R01MH109026 and 1U54HD082013 (GJB).; Boettcher Foundation Webb-Waring Early Career Investigator Award AWD-182937 to J Matthew Taliaferro.; National Institutes of Health 1U54HD082013 to Gary Bassell.; Guild ACORN to Laura I Hudish.; National Institutes of Health NIHAI140044 to Holger A Russ.; Human Islet Research Network NIH/HIRN consortium new investigator award to Holger A Russ.; It was further supported by a Pre-doctoral Training Grant in Molecular Biology (NIH-T32-GM008730) (RG), a Guild ACORN Postdoctoral Fellowship (LIH), and grants from the Colorado Clinical and Translational Science Institute (HAR), the Children’s Diabetes Foundation (HAR), a new investigator award from the NIH/HIRN consortium (HAR), the Culshaw Junior Investigator Award (HAR), and the Juvenile Diabetes Research Foundation (HAR).; National Institutes of Health NIHDK120444 to Holger A Russ.; Colorado Clinical and Translational Sciences Institute to Holger A Russ.; National Institutes of Health NIHDK118803-01A1 to Laura I Hudish.; NIH NIH/HIRN consortium new investigator award to Holger A Russ.; National Institutes of Health NIH1R35GM133885 to J Matthew Taliaferro.; Children's Diabetes Foundation to Holger A Russ.; National Institutes of Health NIH1R01MH109026 to Gary Bassell.; National Institutes of Health NIH-T32-GM008730 to Raeann Goering.
• Keywords: Actin messengers RNA; Regulates translation; Fragile X syndrome; Mental retardation; Life Sciences & Biomedicine; Fish quaint; Science & Technology; G-quartet; In-vivo; binding; Life Sciences & Biomedicine - Other Topics; I304N mutation; Biology; Transport
• Research Categories: Health Sciences, Pharmacology; Chemistry, Biochemistry; Biology, Cell; Biology, Neuroscience

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 30 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.